Human Gene Module / Chromosome 17 / SCN4A

SCN4ASodium channel, voltage gated, type IV alpha subunit

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
7 / 0
Aliases
SCN4A, CMS16,  HOKPP2,  HYKPP,  HYPP,  NAC1A,  Na(V)1.4,  Nav1.4,  SkM1
Associated Syndromes
-
Chromosome Band
17q23.3
Associated Disorders
-
Relevance to Autism

Two de novo missense variants in the SCN4A gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.17) (Iossifov et al., 2014; Krumm et al., 2015).

Molecular Function

This protein mediates the voltage-dependent sodium ion permeability of excitable membranes and may be present in both denervated and innervated skeletal muscle. Mutations in this gene have been linked to several myotonia and periodic paralysis disorders.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SCN4A (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
4 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders Jiao Q , et al. (2019) No -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Omri Bar et al. (2024) Yes ID
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3164T>C p.Ile1055Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4343G>A p.Arg1448His missense_variant De novo - - 30945278 Jiao Q , et al. (2019)
c.4704C>T p.Cys1568%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2370T>A p.Asn790Lys missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.568C>T p.Arg190Trp missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.2587G>A p.Gly863Arg missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.53G>A p.Arg18His missense_variant Familial Paternal Simplex 38256266 Omri Bar et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.17) (Iossifov et al., 2014; Krumm et al., 2015).

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.17) (Iossifov et al., 2014; Krumm et al., 2015).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.17) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[New Scoring Scheme]
4/1/2019
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.17) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.17) (Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
7/1/2015
icon
4

Increased from to 4

Description

Two de novo missense variants in the gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.17) (Iossifov et al., 2014; Krumm et al., 2015).

Krishnan Probability Score

Score 0.4857769085407

Ranking 7300/25841 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 0.010441934669247

Ranking 9970/18225 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 0.94959207573985

Ranking 18153/18665 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 -0.0999353663958

Ranking 12356/20870 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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