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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
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 - et al. () Yes ADD, OCD, ID, learning disability
10 Support - et al. () 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.2827A>C p.Met943Leu missense_variant Unknown - Unknown 38287090 et al. ()
c.3506A>C p.Asn1169Thr missense_variant Familial - Simplex 38256266 et al. ()
c.2185T>C p.Tyr729His missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.4645T>C p.Trp1549Arg missense_variant Familial Paternal Simplex 38256266 et al. ()
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.1964A>G p.Lys655Arg missense_variant Familial Maternal - 27504264 Allen NM , et al. (2016)
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.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

criteria met
See SFARI Gene'scoring criteria
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.
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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