SCN9Asodium voltage-gated channel alpha subunit 9
Autism Reports / Total Reports
5 / 10Rare Variants / Common Variants
36 / 0Aliases
SCN9A, ETHA, FEB3B, GEFSP7, HSAN2D, NE-NA, NENA, Nav1.7, PN1, SFNPAssociated Syndromes
-Chromosome Band
2q24.3Associated 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
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
Strong Candidate
![](https://gene.sfari.org//wp-content/themes/sfari-gene/img/color-band/2.png)
![](https://gene.sfari.org//wp-content/themes/sfari-gene/img/color-band/s-null.png)
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 criteriaWe 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
![icon](https://gene.sfari.org//wp-content/themes/sfari-gene/img/score-same.png)
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](https://gene.sfari.org//wp-content/themes/sfari-gene/img/score-up.png)
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]
ExAC Score
Score 9.3018548424483E-13
Ranking 17359/18225 scored genes
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Sanders TADA Score
Score 0.9490921891627
Ranking 17950/18665 scored genes
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Zhang D Score
Score -0.48903671147735
Ranking 19165/20870 scored genes
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