Human Gene Module / Chromosome 2 / SCN2A

SCN2Asodium channel, voltage-gated, type II, alpha subunit

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
30 / 57
Rare Variants / Common Variants
209 / 0
Aliases
SCN2A, HBA,  NAC2,  HBSCI,  HBSCII,  Nav1.2,  SCN2A1,  SCN2A2,  Na(v)1.2
Associated Syndromes
Dravet syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
2q24.3
Associated Disorders
EPS, EP, ID, ASD, ADHD, DD/NDD
Relevance to Autism

Recurrent mutations in the SCN2A gene have been identified in multiple individuals with ASD as described below. Rare ASD-associated variants in the SCN2A gene were initially identified in a study by Weiss and colleagues in 2003 based on exon screening in a region of linkage with autism (PMID 12610651). Sanders et al., 2012 subsequently reported 2 de novo loss-of-function (LoF) variants in SCN2A among 200 ASD families from the Simons Simplex Collection (PMID 22495306). A third de novo LoF variant in the SCN2A gene was identified in a simplex ASD case in Tavassoli et al., 2014; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was identified in a female ASD proband with intellectual disability in Jiang et al., 2013; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified SCN2A as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Functional analysis of ASD-associated de novo missense and likely gene disruptive SCN2A variants identified in probands from the Simons Simplex Collection and the Autism Sequencing Consortium using whole-cell voltage-clamp electrophysiology in Ben-Shalom et al., 2017 found that these variants dampened or eliminated channel function, consistent with a loss-of-function effect (PMID 28256214). Wolff et al., 2017 reported the phenotypes of 71 previously unpublished patients with SCN2A mutations; ASD was reported as a phenotype in 23 of these patients (PMID 28379373).

Molecular Function

voltage-gated ion channel essential for the generation and propagation of action potentials, chiefly in nerve and muscle.

Reports related to SCN2A (57 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier. Kaplan MR , et al. (2001) No -
2 Highly Cited A missense mutation of the Na channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Sugawara T , et al. (2001) No Febrile seizures
3 Primary Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Weiss LA , et al. (2003) Yes -
4 Highly Cited A targeting motif involved in sodium channel clustering at the axonal initial segment. Garrido JJ , et al. (2003) No -
5 Support A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. Kamiya K , et al. (2004) No Autistic behavior
6 Recent Recommendation The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Tahiliani M , et al. (2007) No -
7 Recent Recommendation Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncod... Martin MS , et al. (2007) No -
8 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
9 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
10 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
11 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Rauch A , et al. (2012) No Epilepsy, ASD
12 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
13 Recent Recommendation Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings. Touma M , et al. (2013) No -
14 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL , et al. (2013) No ID, ASD, DD
15 Support Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Jiang YH , et al. (2013) Yes -
16 Positive Association De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
17 Support Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscula... Baasch AL , et al. (2014) No ID
18 Support De novo SCN2A splice site mutation in a boy with Autism spectrum disorder. Tavassoli T , et al. (2014) Yes -
19 Support De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. EuroEPINOMICS-RES Consortium , et al. (2014) Yes -
20 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
21 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
22 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) Yes DD, ID, epilepsy/seizures
23 Support Whole-genome sequencing of quartet families with autism spectrum disorder. Yuen RK , et al. (2015) Yes -
24 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
25 Support Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders. Codina-Sol M , et al. (2015) Yes -
26 Recent Recommendation Incorporating Functional Information in Tests of Excess De Novo Mutational Load. Jiang Y , et al. (2015) No -
27 Support Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder. Tammimies K , et al. (2015) Yes -
28 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
29 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. D'Gama AM , et al. (2015) Yes -
30 Support Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target? Horvath GA , et al. (2015) Yes Ataxia, hypotonia, cerebral/cerebellar atrophy
31 Recent Recommendation Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Johnson MR , et al. (2015) No -
32 Recent Recommendation Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. Turner TN , et al. (2016) Yes -
33 Recent Recommendation Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a. Calhoun JD , et al. (2016) No -
34 Support Episodic ataxia associated with a de novo SCN2A mutation. Leach EL , et al. (2016) Yes Ataxia, hypotonia, cerebellar atrophy
35 Support Mutations in HECW2 are associated with intellectual disability and epilepsy. Halvardson J , et al. (2016) Yes -
36 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
37 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
38 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
39 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No Hypotonia
40 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Parrini E , et al. (2016) No -
41 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
42 Recent Recommendation Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile ... Ben-Shalom R , et al. (2017) No -
43 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
44 Recent Recommendation Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Wolff M , et al. (2017) No ASD, ID
45 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
46 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Geisheker MR , et al. (2017) Yes -
47 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No -
48 Recent Recommendation Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
49 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
50 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder. Krupp DR , et al. (2017) Yes -
51 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Hamdan FF , et al. (2017) No DD/ID
52 Support Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy. Berecki G , et al. (2018) No -
53 Support Nonsyndromic intellectual disability with novel heterozygous SCN2A mutation and epilepsy. Yokoi T , et al. (2018) No -
54 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
55 Support Autism spectrum disorder and cognitive profile in children with Dravet syndrome: Delineation of a specific phenotype. Ouss L , et al. (2019) No ASD
56 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes. Xiong J , et al. (2019) Yes Epilepsy/seizures
57 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort. Callaghan DB , et al. (2019) Yes DD, ID
Rare Variants   (209)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- p.Trp281Ter stop_gained De novo - - 28379373 Wolff M , et al. (2017)
- p.Arg1235Ter stop_gained De novo - - 28379373 Wolff M , et al. (2017)
- p.Arg1435Ter stop_gained De novo - - 28379373 Wolff M , et al. (2017)
- p.Trp1716Ter stop_gained De novo - - 28379373 Wolff M , et al. (2017)
- - copy_number_loss De novo - Multiplex 25621899 Yuen RK , et al. (2015)
- p.Ala733Thr missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Asp343Gly missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Gly828Val missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Gly882Arg missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Gly882Glu missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.His930Gln missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Ile237Asn missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Ile891Thr missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Leu881Pro missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Phe207Ser missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Phe895Ser missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Ser863Phe missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Thr227Ile missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Val261Met missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Val424Leu missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Val887Ala missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Ala1500Thr missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Ala1652Pro missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Ala1773Val missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Arg1882Pro missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Gln1531Lys missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Gln1811Glu missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Gly1223Arg missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Gly1744Glu missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Ile1281Phe missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Ile1640Ser missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Leu1665Phe missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Lys1933Met missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Met1548Val missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Phe1597Leu missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Pro1622Ser missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Ser1536Arg missense_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Ser1656Phe missense_variant De novo - - 28379373 Wolff M , et al. (2017)
delC - frameshift_variant De novo - Simplex 27525107 Yuen RK , et al. (2016)
c.56G>A p.Arg19Lys missense_variant - - - 11371648 Sugawara T , et al. (2001)
c.1819C>T p.Arg607Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.2566C>T p.Arg856Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.304C>T p.Arg102Ter stop_gained De novo - - 15028761 Kamiya K , et al. (2004)
c.868A>G p.Ile290Val missense_variant De novo - - 28831199 Li J , et al. (2017)
c.3850-2A>C p.? splice_site_variant De novo - - 27824329 Wang T , et al. (2016)
c.386+2T>C p.? splice_site_variant De novo - - 28379373 Wolff M , et al. (2017)
c.605+1G>T p.? splice_site_variant De novo - - 28379373 Wolff M , et al. (2017)
c.698-1G>T p.? splice_site_variant De novo - - 28379373 Wolff M , et al. (2017)
c.1571G>A p.Arg524Gln missense_variant - - - 11371648 Sugawara T , et al. (2001)
c.1429G>T p.Ala477Ser missense_variant De novo - - 28831199 Li J , et al. (2017)
c.5318C>T p.Ala1773Val missense_variant De novo - - 28831199 Li J , et al. (2017)
c.4193G>A p.Trp1398Ter stop_gained De novo - - 23033978 de Ligt J , et al. (2012)
- - copy_number_loss Familial Maternal Simplex 26749308 Turner TN , et al. (2016)
- p.Arg583Ter stop_gained De novo - Simplex 25969726 Codina-Sol M , et al. (2015)
c.2197G>C p.Ala733Pro missense_variant Unknown - - 27824329 Wang T , et al. (2016)
c.788C>T p.Ala263Val missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.2566C>T p.Arg856Ter stop_gained De novo - Simplex 30564305 Guo H , et al. (2018)
c.3956G>C p.Arg1319Pro missense_variant De novo - - 27824329 Wang T , et al. (2016)
- p.Ala202Val missense_variant Familial Maternal - 28379373 Wolff M , et al. (2017)
c.1267G>C p.Val423Leu missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.1289A>C p.Glu430Ala missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.1835T>C p.Phe612Ser missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.2558G>A p.Arg853Gln missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.2558G>A p.Arg853Gln missense_variant Unknown - - 28379373 Wolff M , et al. (2017)
c.2567G>A p.Arg856Gln missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.2695G>A p.Gly899Ser missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.2722A>G p.Lys908Glu missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.2995G>A p.Glu999Lys missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.2558G>A p.Arg853Gln missense_variant De novo - - 28708303 Chrot E , et al. (2017)
- p.Asn503LysfsTer19 frameshift_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Thr1711LeufsTer8 frameshift_variant De novo - - 28379373 Wolff M , et al. (2017)
- p.Val1528CysfsTer7 frameshift_variant De novo - - 28379373 Wolff M , et al. (2017)
c.4303C>T p.Arg1435Ter stop_gained De novo - Simplex 30564305 Guo H , et al. (2018)
c.605+1G>A p.? splice_site_variant De novo - Simplex 30564305 Guo H , et al. (2018)
- p.Phe1651Cys missense_variant De novo (mosaic) - - 28379373 Wolff M , et al. (2017)
c.3631G>A p.Glu1211Lys missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.3955C>T p.Arg1319Trp missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.3956G>A p.Arg1319Gln missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.3956G>A p.Arg1319Gln missense_variant Unknown - - 28379373 Wolff M , et al. (2017)
c.4025T>C p.Leu1342Pro missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.4633A>G p.Met1545Val missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.4879G>A p.Val1627Met missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.4886G>A p.Arg1629His missense_variant De novo - - 28379373 Wolff M , et al. (2017)
c.5645G>T p.Arg1882Gln missense_variant Unknown - - 28379373 Wolff M , et al. (2017)
c.4501A>G p.Met1501Val missense_variant De novo - - 31031587 Xiong J , et al. (2019)
- p.Cys1170ValfsTer15 frameshift_variant De novo - - 28379373 Wolff M , et al. (2017)
c.571T>G p.Trp191Gly missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.751G>A p.Val251Ile missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.788C>T p.Ala263Val missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.83G>A p.Arg28His missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2687C>T p.Ala896Val missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.408G>T p.Met136Ile missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
G>A p.Gly1634Asp missense_variant De novo - Simplex 27328862 Leach EL , et al. (2016)
c.3947C>T p.Ala1316Val missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.3967A>G p.Met1323Val missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.4031G>A p.Cys1344Tyr missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.4643T>C p.Met1548Thr missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.5645G>A p.Arg1882Gln missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.4551+1G>C - splice_site_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.2715G>C p.Lys905Asn missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.2783T>G p.Phe928Cys missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.578G>C p.Trp193Ser missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1094C>T p.Thr365Met missense_variant De novo - Simplex 28831199 Li J , et al. (2017)
c.5704C>T p.Arg1902Cys missense_variant - - Multiplex 12610651 Weiss LA , et al. (2003)
c.1819C>T p.Arg607Ter stop_gained Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
c.5645G>A p.Arg1882Gln missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.4468A>G p.Met1490Val missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.4726G>A p.Gly1576Arg missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.476+1G>A - splice_site_variant De novo - Simplex 24650168 Tavassoli T , et al. (2014)
c.1034G>A p.Gly345Asp missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.1184G>C p.Arg395Pro missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.2764C>T p.Arg922Cys missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.2810G>A p.Arg937His missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.4543C>T p.Arg1515Ter stop_gained Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.1959G>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2877C>A p.Cys959Ter stop_gained De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.4409G>C p.Gly1470Ala missense_variant De novo - - 26325558 Tammimies K , et al. (2015)
c.4823-2A>T - splice_site_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1060G>A p.Val354Met missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1067C>G p.Ala356Gly missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1112G>T p.Ser371Ile missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1136G>A p.Arg379His missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1165C>T p.Leu389Phe missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.2482G>A p.Gly828Ser missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.2764C>T p.Arg922Cys missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.2809C>T p.Arg937Cys missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.2810G>A p.Arg937His missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.2860G>A p.Ala954Thr missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.5522C>T p.Ala1841Val missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.4461C>G p.Asp1487Glu missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.4904G>A p.Arg1635Gln missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.5230G>A p.Gly1744Arg missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.5274T>G p.Ser1758Arg missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.5316C>G p.Ile1772Met missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.232dup p.Leu78ProfsTer11 frameshift_variant De novo - - 27824329 Wang T , et al. (2016)
c.3037G>T p.Gly1013Ter stop_gained De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.1081delA p.Asn361fs frameshift_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.305G>A p.Arg102Gln missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.106A>G p.Arg36Gly missense_variant Familial Maternal - 28379373 Wolff M , et al. (2017)
c.2809C>T p.Arg937Cys missense_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.2809C>T p.Arg937Cys missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.5230G>T p.Gly1744Ter stop_gained Unknown - Multiplex 28263302 C Yuen RK , et al. (2017)
c.34G>A p.Asp12Asn missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.4474G>T p.Glu1492Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4876C>T p.Arg1626Ter stop_gained De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.476+1G>A p.? splice_site_variant De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.4504delA p.Lys1502fs frameshift_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.4156T>C p.Cys1386Arg missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.4378G>C p.Gly1460Arg missense_variant De novo - Simplex 30062040 Yokoi T , et al. (2018)
c.781G>A p.Val261Met missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.82C>T p.Arg28Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3827G>A p.Trp1276Ter stop_gained De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.971-1G>A p.? splice_site_variant De novo - Simplex 31038196 Callaghan DB , et al. (2019)
c.2021C>A p.Thr674Lys missense_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.245A>G p.Asp82Gly missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.100G>A p.Ala34Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2558G>A p.Arg853Gln missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.5377G>A p.Asp1793Asn missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.5645G>T p.Arg1882Leu missense_variant De novo - Simplex 24579881 Baasch AL , et al. (2014)
c.5230G>A p.Gly1744Arg missense_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.4468A>G p.Met1490Val missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.4886G>A p.Arg1629His missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.148C>T p.Pro50Ser missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.193A>G p.Ile65Val missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.1302_1303del p.Ala434fs frameshift_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.4259C>T p.Thr1420Met missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.1136G>A p.Arg379His missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2810G>A p.Arg937His missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.788C>T p.Ala263Val missense_variant De novo - Simplex 27334371 Halvardson J , et al. (2016)
c.305G>A p.Arg102Gln missense_variant De novo - Simplex 31038196 Callaghan DB , et al. (2019)
c.4794_4795del p.Asp1598fs frameshift_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.4875delC p.Phe1625fs frameshift_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.2050C>T p.Arg684Trp missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.4822G>A p.Gly1608Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5704C>T p.Arg1902Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
- - copy_number_gain De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.605+1G>A p.? splice_site_variant Unknown Not maternal Simplex 30564305 Guo H , et al. (2018)
c.1821_1822del p.Asp609LeufsTer37 frameshift_variant De novo - - 27824329 Wang T , et al. (2016)
c.4796_4797del p.Phe1599CysfsTer14 frameshift_variant De novo - - 27824329 Wang T , et al. (2016)
c.5711_5712del p.Gln1904ArgfsTer22 frameshift_variant De novo - - 27824329 Wang T , et al. (2016)
c.4160_4161del p.Lys1387SerfsTer4 frameshift_variant De novo - - 28379373 Wolff M , et al. (2017)
c.82C>T p.Arg28Cys missense_variant Familial Maternal Simplex 23849776 Jiang YH , et al. (2013)
c.3057delA p.Ile1021TyrfsTer16 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.1094C>T p.Thr365Met missense_variant Familial Maternal - 28628100 Geisheker MR , et al. (2017)
c.5333del p.Asn1778fs frameshift_variant De novo - Simplex 27479843 Lelieveld SH , et al. (2016)
c.3670G>T p.Ala1224Ser missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.1315_1346del p.Ala439fs frameshift_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.3598A>G p.Thr1200Ala missense_variant Familial - Multiplex 25363760 De Rubeis S , et al. (2014)
c.1508dup p.Asn503LysfsTer19 frameshift_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.1561_1562del p.Asp521fs frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3370A>T p.Ser1124Cys missense_variant Familial Maternal Simplex 28867142 Krupp DR , et al. (2017)
c.1317_1348del p.440_450del frameshift_variant De novo - Multiplex 23849776 Jiang YH , et al. (2013)
c.562C>T p.Arg188Trp missense_variant Familial Paternal Simplex 11371648 Sugawara T , et al. (2001)
c.2057_2058insA p.Ser686fs frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.4578delT p.Asp1526fs frameshift_variant Unknown Not maternal Simplex 30564305 Guo H , et al. (2018)
c.1831_1832del p.Leu611ValfsTer35 frameshift_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.2545C>A p.Leu849Ile missense_variant Familial Paternal Simplex 28628100 Geisheker MR , et al. (2017)
c.2379+1G>A p.Glu717GlyfsTer30 splice_site_variant De novo - Simplex 26647175 Horvath GA , et al. (2015)
c.3929_3930delCTinsT p.Ala1310ValfsTer2 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.605+1G>A - splice_site_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.304C>T p.Arg102Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.4509_4510delinsT p.Lys1503AsnfsTer26 frameshift_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.4264A>G p.Lys1422Glu missense_variant De novo - Simplex 25262651 EuroEPINOMICS-RES Consortium , et al. (2014)
c.2932T>C p.Phe978Leu missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.4780T>A p.Trp1594Arg missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.5638G>A p.Glu1880Lys missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1435_1437delGGGinsGG p.Ile480Ter frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.515T>G p.Ile172Ser missense_variant Familial Maternal Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
c.1694_1696delCCCinsCC p.Leu566PhefsTer75 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

1

Score Delta: Score remained at 1.1

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2017
1
icon
1

Score remained at 1

Description

Rare ASD-associated variants in the SCN2A gene were initially identified in a study by Weiss and colleagues in 2003 based on exon screening in a region of linkage with autism (PMID 12610651). Sanders et al., 2012 subsequently reported 2 de novo loss-of-function (LoF) variants in SCN2A among 200 ASD families from the Simons Simplex Collection (PMID 22495306). A third de novo LoF variant in the SCN2A gene was identified in a simplex ASD case in Tavassoli et al., 2014; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was identified in a female ASD proband with intellectual disability in Jiang et al., 2013; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified SCN2A as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Functional analysis of ASD-associated de novo missense and likely gene disruptive SCN2A variants identified in probands from the Simons Simplex Collection and the Autism Sequencing Consortium using whole-cell voltage-clamp electrophysiology in Ben-Shalom et al., 2017 found that these variants dampened or eliminated channel function, consistent with a loss-of-function effect (PMID 28256214). Wolff et al., 2017 reported the phenotypes of 71 previously unpublished patients with SCN2A mutations; ASD was reported as a phenotype in 23 of these patients (PMID 28379373).

7/1/2017
1
icon
1

Score remained at 1

Description

Rare ASD-associated variants in the SCN2A gene were initially identified in a study by Weiss and colleagues in 2003 based on exon screening in a region of linkage with autism (PMID 12610651). Sanders et al., 2012 subsequently reported 2 de novo loss-of-function (LoF) variants in SCN2A among 200 ASD families from the Simons Simplex Collection (PMID 22495306). A third de novo LoF variant in the SCN2A gene was identified in a simplex ASD case in Tavassoli et al., 2014; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was identified in a female ASD proband with intellectual disability in Jiang et al., 2013; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified SCN2A as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Functional analysis of ASD-associated de novo missense and likely gene disruptive SCN2A variants identified in probands from the Simons Simplex Collection and the Autism Sequencing Consortium using whole-cell voltage-clamp electrophysiology in Ben-Shalom et al., 2017 found that these variants dampened or eliminated channel function, consistent with a loss-of-function effect (PMID 28256214). Wolff et al., 2017 reported the phenotypes of 71 previously unpublished patients with SCN2A mutations; ASD was reported as a phenotype in 23 of these patients (PMID 28379373).

4/1/2017
1
icon
1

Score remained at 1

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LoF in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SCN2A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Functional analysis of ASD-associated de novo missense and likely gene disruptive SCN2A variants identified in probands from the Simons Simplex Collection and the Autism Sequencing Consortium using whole-cell voltage-clamp electrophysiology in Ben-Shalom et al., 2017 found that these variants dampened or eliminated channel function, consistent with a loss-of-function effect. Wolff et al., 2017 reported the phenotypes of 71 previously unpublished patients with SCN2A mutations; ASD was reported as a phenotype in 23 of these patients.

Reports Added
[Sodium channels SCN1A, SCN2A and SCN3A in familial autism.2003] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [De novo SCN2A splice site mutation in a boy with Autism spectrum disorder.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscula...2014] [A missense mutation of the Na channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction.2001] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier.2001] [A targeting motif involved in sodium channel clustering at the axonal initial segment.2003] [The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation.2007] [Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncod...2007] [Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings.2013] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Excess of rare, inherited truncating mutations in autism.2015] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.2016] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a.2016] [Mutations in HECW2 are associated with intellectual disability and epilepsy.2016] [Episodic ataxia associated with a de novo SCN2A mutation.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016] [Genome-wide characteristics of de novo mutations in autism.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016] [Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile ...2017] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017] [Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
1
icon
1

Score remained at 1

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LoF in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SCN2A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Functional analysis of ASD-associated de novo missense and likely gene disruptive SCN2A variants identified in probands from the Simons Simplex Collection and the Autism Sequencing Consortium using whole-cell voltage-clamp electrophysiology in Ben-Shalom et al., 2017 found that these variants dampened or eliminated channel function, consistent with a loss-of-function effect.

10/1/2016
1
icon
1

Score remained at 1

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LoF in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SCN2A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

7/1/2016
1
icon
1

Score remained at 1

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LoF in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SCN2A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

4/1/2016
1
icon
1

Score remained at 1

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LoF in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SCN2A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Sodium channels SCN1A, SCN2A and SCN3A in familial autism.2003] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [De novo SCN2A splice site mutation in a boy with Autism spectrum disorder.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscula...2014] [A missense mutation of the Na channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction.2001] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier.2001] [A targeting motif involved in sodium channel clustering at the axonal initial segment.2003] [The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation.2007] [Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncod...2007] [Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings.2013] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Excess of rare, inherited truncating mutations in autism.2015] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.2016] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a.2016]
1/1/2016
1
icon
1

Score remained at 1

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LoF in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SCN2A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Sodium channels SCN1A, SCN2A and SCN3A in familial autism.2003] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [De novo SCN2A splice site mutation in a boy with Autism spectrum disorder.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscula...2014] [A missense mutation of the Na channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction.2001] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier.2001] [A targeting motif involved in sodium channel clustering at the axonal initial segment.2003] [The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation.2007] [Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncod...2007] [Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings.2013] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Excess of rare, inherited truncating mutations in autism.2015] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.2016] [The contribution of de novo coding mutations to autism spectrum disorder.2014]
7/1/2015
1
icon
1

Score remained at 1

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LoF in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SCN2A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

Reports Added
[Sodium channels SCN1A, SCN2A and SCN3A in familial autism.2003] [De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [De novo SCN2A splice site mutation in a boy with Autism spectrum disorder.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscula...2014] [A missense mutation of the Na channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction.2001] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier.2001] [A targeting motif involved in sodium channel clustering at the axonal initial segment.2003] [The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation.2007] [Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncod...2007] [Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings.2013] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Excess of rare, inherited truncating mutations in autism.2015] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015]
4/1/2015
1
icon
1

Score remained at 1

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LoF in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SCN2A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

1/1/2015
1
icon
1

Score remained at 1

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LGD in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SCN2A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

10/1/2014
2
icon
1

Decreased from 2 to 1

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LGD in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SCN2A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

7/1/2014
No data
icon
2

Increased from No data to 2

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LGD in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776).

4/1/2014
No data
icon
2

Increased from No data to 2

Description

Rare variants in the SCN2A gene were identified in a single study based on exon screening in a region of linkage with autism (PMID: 12610651). PMID 22495306 reported 2 de novo LGD in SCN2A among 200 ASD families. A third de novo LoF variant in the SCN2A gene was recently identified in a simplex ASD case; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was recently identified in a female ASD proband with intellectual disability; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776).

Krishnan Probability Score

Score 0.6089135525395

Ranking 272/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99999999231438

Ranking 132/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.998

Ranking 10/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 3.5684477595055E-10

Ranking 2/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 120

Ranking 6/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.53627129374455

Ranking 302/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with SCN2A(1 CNVs)
2q24.3 16 Deletion 28  /  100
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ARHGEF10L Rho guanine nucleotide exchange factor (GEF) 10-like Human Protein Binding 55160 Q9HCE6
FGF14 fibroblast growth factor 14 Human Direct Regulation 2259 Q92915
Scn4b sodium channel, voltage-gated, type IV, beta Rat Protein Binding 315611 Q7M730
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