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
21 / 40
Rare Variants / Common Variants
89 / 0
Aliases
SCN2A, HBA,  NAC2,  HBSCI,  HBSCII,  Nav1.2,  SCN2A1,  SCN2A2,  Na(v)1.2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
2q24.3
Associated Disorders
ASD, EPS, DD/NDD, ADHD, ID, EP
Relevance to Autism

Rare variants in the SCN2A gene have been identified with autism (Weiss et al., 2003; Sanders et al., 2012) as well as with febrile seizures (Sugawara et al., 2001).

Molecular Function

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

Reports related to SCN2A (40 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 Recent Recommendation The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Tahiliani M , et al. (2007) No -
6 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 -
7 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
8 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
9 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
10 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
11 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
12 Recent Recommendation Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings. Touma M , et al. (2013) No -
13 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL , et al. (2013) No ID, ASD, DD
14 Support Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Jiang YH , et al. (2013) Yes -
15 Positive association De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
16 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
17 Support De novo SCN2A splice site mutation in a boy with Autism spectrum disorder. Tavassoli T , et al. (2014) Yes -
18 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
19 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
20 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) Yes DD, ID, epilepsy/seizures
21 Support Whole-genome sequencing of quartet families with autism spectrum disorder. Yuen RK , et al. (2015) Yes -
22 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
23 Support Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders. Codina-Sol M , et al. (2015) Yes -
24 Recent recommendation Incorporating Functional Information in Tests of Excess De Novo Mutational Load. Jiang Y , et al. (2015) No -
25 Support Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder. Tammimies K , et al. (2015) Yes -
26 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
27 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. D'Gama AM , et al. (2015) Yes -
28 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
29 Recent recommendation Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Johnson MR , et al. (2015) No -
30 Recent recommendation Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. Turner TN , et al. (2016) Yes -
31 Recent recommendation Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a. Calhoun JD , et al. (2016) No -
32 Support Episodic ataxia associated with a de novo SCN2A mutation. Leach EL , et al. (2016) Yes Ataxia, hypotonia, cerebellar atrophy
33 Support Mutations in HECW2 are associated with intellectual disability and epilepsy. Halvardson J , et al. (2016) Yes -
34 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
35 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
36 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
37 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No Hypotonia
38 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 -
39 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
40 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 -
Rare Variants   (89)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.562C>T p.Arg188Trp missense_variant Familial Paternal Simplex 11371648 Sugawara T , et al. (2001)
c.1571G>A p.Arg524Gln missense_variant - - - 11371648 Sugawara T , et al. (2001)
c.56G>A p.Arg19Lys missense_variant - - - 11371648 Sugawara T , et al. (2001)
c.5704C>T p.Arg1902Cys missense_variant - - Multiplex 12610651 Weiss LA , et al. (2003)
c.1959G>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.5377G>A p.Asp1793Asn missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.3037G>T p.Gly1013Ter stop_gained De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.2877C>A p.Cys959Ter stop_gained De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.4259C>T p.Thr1420Met missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.1831_1832del p.Leu611ValfsTer35 frameshift_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.1508dup p.Asn503LysfsTer19 frameshift_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.2809C>T p.Arg937Cys missense_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.4193G>A p.Trp1398Ter stop_gained De novo - - 23033978 de Ligt J , et al. (2012)
c.408G>T p.Met136Ile missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
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.3057delA p.Ile1021TyrfsTer16 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.5645G>A p.Arg1882Gln missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.1317_1348del p.440_450del frameshift_variant De novo - Multiplex 23849776 Jiang YH , et al. (2013)
c.82C>T p.Arg28Cys missense_variant Familial Maternal Simplex 23849776 Jiang YH , et al. (2013)
c.2558G>A p.Arg853Gln missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.5645G>T p.Arg1882Leu missense_variant De novo - Simplex 24579881 Baasch AL , et al. (2014)
c.476+1G>A - splice_site_variant De novo - Simplex 24650168 Tavassoli T , et al. (2014)
c.2057_2058insA p.Ser686fs frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.4823-2A>T - splice_site_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.245A>G p.Asp82Gly missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1136G>A p.Arg379His missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
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.193A>G p.Ile65Val missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.3598A>G p.Thr1200Ala missense_variant Familial - Multiplex 25363760 De Rubeis S , et al. (2014)
c.148C>T p.Pro50Ser missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.2050C>T p.Arg684Trp missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.2050C>T p.Arg684Trp missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.4474G>T p.Glu1492Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1561_1562del p.Asp521fs frameshift_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)
c.82C>T p.Arg28Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.100G>A p.Ala34Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4822G>A p.Gly1608Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.34G>A p.Asp12Asn missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1435_1437delGGGinsGG p.Ile480Ter frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1694_1696delCCCinsCC p.Leu566PhefsTer75 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.605+1G>A - splice_site_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2932T>C p.Phe978Leu missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
- - copy_number_gain 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.304C>T p.Arg102Ter stop_gained 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.515T>G p.Ile172Ser missense_variant Familial Maternal Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
- - copy_number_loss De novo - Multiplex 25621899 Yuen RK , et al. (2015)
c.2809C>T p.Arg937Cys missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.4156T>C p.Cys1386Arg missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
- p.Arg583Ter stop_gained De novo - Simplex 25969726 Codina-Sol M , et al. (2015)
c.4409G>C p.Gly1470Ala missense_variant De novo - - 26325558 Tammimies K , et al. (2015)
c.2021C>A p.Thr674Lys missense_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.5230G>A p.Gly1744Arg missense_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.4551+1G>C - splice_site_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.4543C>T p.Arg1515Ter stop_gained Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.2379+1G>A p.Glu717GlyfsTer30 splice_site_variant De novo - Simplex 26647175 Horvath GA , et al. (2015)
- - copy_number_loss Familial Maternal Simplex 26749308 Turner TN , et al. (2016)
G>A p.Gly1634Asp missense_variant De novo - Simplex 27328862 Leach EL , et al. (2016)
c.788C>T p.Ala263Val missense_variant De novo - Simplex 27334371 Halvardson J , et al. (2016)
c.5333del p.Asn1778fs frameshift_variant De novo - Simplex 27479843 Lelieveld SH , et al. (2016)
delC - frameshift_variant De novo - Simplex 27525107 Yuen RK , et al. (2016)
c.232dup p.Leu78ProfsTer11 frameshift_variant De novo - - 27824329 Wang T , et al. (2016)
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.3850-2A>C p.? splice_site_variant De novo - - 27824329 Wang T , et al. (2016)
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.3956G>C p.Arg1319Pro missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.4509_4510delinsT p.Lys1503AsnfsTer26 frameshift_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.305G>A p.Arg102Gln missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.2197G>C p.Ala733Pro missense_variant Unknown - - 27824329 Wang T , et al. (2016)
c.3827G>A p.Trp1276Ter stop_gained De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.3967A>G p.Met1323Val 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.788C>T p.Ala263Val missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.571T>G p.Trp191Gly missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.2687C>T p.Ala896Val missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.3947C>T p.Ala1316Val 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.4031G>A p.Cys1344Tyr 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.3929_3930delCTinsT p.Ala1310ValfsTer2 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.476+1G>A p.? splice_site_variant De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.4876C>T p.Arg1626Ter stop_gained De novo - Simplex 28191889 Stessman HA , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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.

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.

01-01-2017
1

Initial score established: 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.

CNVs associated with SCN2A(1 CNVs)
2q24.3 10 Deletion 21  /  93
Animal Models associated with SCN2A(3 Models)
SCN2A_1_KO_HM Genetic
SCN2A_2_KO_HT Genetic
SCN2A_3_Q54_HM Genetic
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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