Human Gene Module / Chromosome 2 / SCN9A

SCN9Asodium voltage-gated channel alpha subunit 9

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 10
Rare Variants / Common Variants
36 / 0
Aliases
SCN9A, ETHA,  FEB3B,  GEFSP7,  HSAN2D,  NE-NA,  NENA,  Nav1.7,  PN1,  SFNP
Associated Syndromes
-
Chromosome Band
2q24.3
Associated Disorders
-
Relevance to Autism

Whole-exome sequencing of five families in which second- and third-degree relatives were affected with autism identified a novel private missense variant (p.Cys1143Phe) in the second intracellular loop of the Nav1.7 sodium channel (encoded by the SCN9A gene) that exhibited partial loss-of-function effects. An excess of rare missense variants in the same intracellular loop was subsequently observed in a case-control variant-burden study of 1004 familial ASD cases and 1127 controls (29 in cases vs. 2 in controls; P=5.1E-07), with one of the variants (p.Met932Leu/Val991Leu) also showing functional effects (Rubinstein et al., 2016).

Molecular Function

Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na+ions may pass in accordance with their electrochemical gradient. Plays a role in pain mechanisms, especially in the development of inflammatory pain.

SFARI Genomic Platforms
Reports related to SCN9A (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome Singh NA , et al. (2009) No Febrile seizures
2 Support Whole-genome sequencing of quartet families with autism spectrum disorder Yuen RK , et al. (2015) Yes -
3 Support Atypical benign partial epilepsy of childhood with acquired neurocognitive, lexical semantic, and autistic spectrum disorder Allen NM , et al. (2016) No -
4 Primary Association of rare missense variants in the second intracellular loop of Na V 1.7 sodium channels with familial autism Rubinstein M , et al. (2016) Yes -
5 Support Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment Chen XS , et al. (2017) No -
6 Support - Chuan Z et al. (2022) No -
7 Support - Zhou X et al. (2022) Yes -
8 Support - Sanchis-Juan A et al. (2023) No -
9 Support - Omri Bar et al. (2024) Yes ADD, OCD, ID, learning disability
10 Support - Duyen T Bui et al. (2024) Yes -
Rare Variants   (36)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.640C>T p.Arg214Ter stop_gained Unknown - - 35571021 Chuan Z et al. (2022)
c.2185T>C p.Tyr729His missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.129T>C p.Asp43%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4226C>T p.Thr1409Met missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3734A>G p.Asn1245Ser missense_variant Familial - Simplex 28440294 Chen XS , et al. (2017)
c.3799C>G p.Leu1267Val missense_variant Familial - Simplex 28440294 Chen XS , et al. (2017)
c.3506A>C p.Asn1169Thr missense_variant Familial - Simplex 38256266 Omri Bar et al. (2024)
c.1964A>G p.Lys655Arg missense_variant Familial Maternal - 27504264 Allen NM , et al. (2016)
c.2827A>C p.Met943Leu missense_variant Unknown - Unknown 38287090 Duyen T Bui et al. (2024)
c.4522A>G p.Ile1508Val missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.5131C>T p.Pro1711Ser missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.2391G>A p.Trp797Ter stop_gained Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3449G>A p.Arg1150Gln stop_gained Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.4645T>C p.Trp1549Arg missense_variant Familial Paternal Simplex 38256266 Omri Bar et al. (2024)
c.554G>A p.Arg185His missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.684C>G p.Ile228Met missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.1921A>T p.Asn641Tyr missense_variant Familial - Multi-generational 19763161 Singh NA , et al. (2009)
c.1115G>A p.Arg372His missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.1469G>A p.Ser490Asn missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.1846G>A p.Gly616Arg missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.1940A>T p.Glu647Val missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.2215A>G p.Ile739Val missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.2271G>A p.Met757Ile missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.2794A>C p.Met932Leu missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.2971G>T p.Val991Leu missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3092C>T p.Thr1031Ile missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3136G>A p.Asp1046Asn missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3328C>T p.Arg1110Trp missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3369G>T p.Leu1123Phe missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3523T>A p.Tyr1175Asn missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3799C>G p.Leu1267Val missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.4040G>A p.Arg1347Gln missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.4282G>A p.Val1428Ile missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.4612C>T p.Trp1538Arg missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.298_299dup p.Asn101SerfsTer16 frameshift_variant Familial Paternal Multiplex 25621899 Yuen RK , et al. (2015)
c.3428G>T p.Cys1143Phe missense_variant Familial Unknown Extended multiplex 27956748 Rubinstein M , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Whole-exome sequencing of five families in which second- and third-degree relatives were affected with autism identified a novel private missense variant (p.Cys1143Phe) in the second intracellular loop of the Nav1.7 sodium channel (encoded by the SCN9A gene) that exhibited partial loss-of-function effects. An excess of rare missense variants in the same intracellular loop was subsequently observed in a case-control variant-burden study of 1004 familial ASD cases and 1127 controls (29 in cases vs. 2 in controls; P=5.1E-07), with one of the variants (p.Met932Leu/Val991Leu) also showing functional effects (Rubinstein et al., 2016). Inherited variants in SCN9A had previously been identified in both affected siblings of a multiplex ASD family (Yuen et al., 2015), as well as in a male proband with atypical benign partial epilepsy (ABPE) of childhood and a diagnosis of PDD-NOS (Allen et al., 2016). Singh et al., 2009 identified a functional missense variant in SCN9A that segregated with febrile seizures in a large Utah family with 21 affected members; in the same report, it was suggested that SCN9A could act as a potential modifier of Dravet syndrome.

Score Delta: Score remained at 2

2

Strong Candidate

See all Category 2 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.

10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
Description

Whole-exome sequencing of five families in which second- and third-degree relatives were affected with autism identified a novel private missense variant (p.Cys1143Phe) in the second intracellular loop of the Nav1.7 sodium channel (encoded by the SCN9A gene) that exhibited partial loss-of-function effects. An excess of rare missense variants in the same intracellular loop was subsequently observed in a case-control variant-burden study of 1004 familial ASD cases and 1127 controls (29 in cases vs. 2 in controls; P=5.1E-07), with one of the variants (p.Met932Leu/Val991Leu) also showing functional effects (Rubinstein et al., 2016). Inherited variants in SCN9A had previously been identified in both affected siblings of a multiplex ASD family (Yuen et al., 2015), as well as in a male proband with atypical benign partial epilepsy (ABPE) of childhood and a diagnosis of PDD-NOS (Allen et al., 2016). Singh et al., 2009 identified a functional missense variant in SCN9A that segregated with febrile seizures in a large Utah family with 21 affected members; in the same report, it was suggested that SCN9A could act as a potential modifier of Dravet syndrome.

Reports Added
[New Scoring Scheme]
1/1/2017
icon
2

Increased from to 2

Description

Whole-exome sequencing of five families in which second- and third-degree relatives were affected with autism identified a novel private missense variant (p.Cys1143Phe) in the second intracellular loop of the Nav1.7 sodium channel (encoded by the SCN9A gene) that exhibited partial loss-of-function effects. An excess of rare missense variants in the same intracellular loop was subsequently observed in a case-control variant-burden study of 1004 familial ASD cases and 1127 controls (29 in cases vs. 2 in controls; P=5.1E-07), with one of the variants (p.Met932Leu/Val991Leu) also showing functional effects (Rubinstein et al., 2016). Inherited variants in SCN9A had previously been identified in both affected siblings of a multiplex ASD family (Yuen et al., 2015), as well as in a male proband with atypical benign partial epilepsy (ABPE) of childhood and a diagnosis of PDD-NOS (Allen et al., 2016). Singh et al., 2009 identified a functional missense variant in SCN9A that segregated with febrile seizures in a large Utah family with 21 affected members; in the same report, it was suggested that SCN9A could act as a potential modifier of Dravet syndrome.

Krishnan Probability Score

Score 0.49180716478139

Ranking 5055/25841 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 9.3018548424483E-13

Ranking 17359/18225 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
Sanders TADA Score

Score 0.9490921891627

Ranking 17950/18665 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).
Zhang D Score

Score -0.48903671147735

Ranking 19165/20870 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.
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