GeneBe

SCN2A

protein-coding

sodium voltage-gated channel alpha subunit 2, the group of Sodium voltage-gated channel alpha subunits

Gene summary

Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

Previous symbols:
  • SCN2A1
  • SCN2A2

MANE transcript

NM_001040142.2

Inheritance

AD

ClinVar variants

P:733U:1181B:614

Top phenotype

Developmental and epileptic encephalopathy 11; Seizures, benign familial infantile, 3; Episodic ataxia, type 9

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr2:165,194,993-165,392,310

External References & Databases

Ensembl (ENSG00000136531)NCBI Gene (6326)OMIM (182390)HGNC:10588GenCCUniProt (Q99250)AlphaFoldClinVar (SCN2A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~197.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Dravet syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011794

Submitter: Orphanet

genetic developmental and epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Orphanet

benign familial infantile epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017615

Submitter: Orphanet

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Illumina

seizures, benign familial infantile, 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011904

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 11DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013388

Submitter: Ambry Genetics

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

seizures, benign familial infantile, 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011904

Submitter: Labcorp Genetics (formerly Invitae)

episodic ataxia, type 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030064

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013388

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: G2P

developmental and epileptic encephalopathy, 11DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013388

Submitter: G2P

malignant migrating partial seizures of infancySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017385

Submitter: Orphanet

benign familial neonatal-infantile seizuresSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011140

Submitter: Orphanet

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Variation in SCN2A was first reported in relation to complex neurodevelopmental disorder in 2001 (Sugawara et al., PMID 11371648); variants in affected individuals were observed in the heterozygous state (consistent with autosomal dominant mode of inheritance), though most cases are de novo. At least 98 variants (e.g. missense, nonsense, frameshift, splice site) have been reported in humans: 8 variants in individuals with infantile seizures and developmental delay, 51 variants in epileptic encephalopathy with infantile seizures and developmental delay, hypotonia, cerebral atrophy, 39 variants with developmental disorder or autism spectrum disorder/intellectual disability (Ben Shalom et al. 2017 PMID 28256214). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is insufficient evidence of a difference in molecular mechanisms or inheritance pattern despite genotype:phenotype correlations that may explain the wide phenotypic spectrum observed from SCN2A variation (PMID 28256214, http://epilepsygenetics.net/2015/08/11/scn2a-this-is-what-you-need-to-know-in-2015/); therefore, we decided to curate all of these entities together under the umbrella term “complex neurodevelopmental disorder.” Of note, this gene has also been implicated in benign infantile familial seizures (MONDO:0011140). These cases will be assessed in a separate curation. Evidence supporting the relationship between SCN2A and complex neurodevelopmental disorder includes case-level data and experimental data. For the purposes of this curation, 11 variants in this gene were scored in the following 8 publications: PMIDs 19786696, 23662938, 15028761, 30185235, 20956790, 24650168, 23935176, 22495306. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, both loss-of-function and gain-of-function of SCN2A have been observed in experiments with patient variants (PMIDs 28379373, 29867081). This gene-disease association is supported by mouse models, functional alteration, and expression studies (PMIDs 24267886, 30144217, 28256214, 28379373, 29867081). In summary, SCN2A variation is definitively associated with complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Expert Panel on 5/7/2019 (SOP Version 6).

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 11; Seizures, benign familial infantile, 3; Episodic ataxia, type 9AD

Manifestation: Neurologic

Intervention: Neurologic

Rationale: In Epileptic encephalopathy, early infantile, 11 and Seizures, benign familial infantile, 3, individuals may manifest with seizures (among other findings), and specific knowledge of the underlying cause can help direct selection of optimal therapies for management based on the genetic etiology; In Episodic ataxia, type 9, individuals manifest with ataxic episodes, and treatment with acetazolamide has been reported to be effective in some patients

Refs: 6660252; 3508699; 8734025; 11326335; 15048894; 15028761; 19786696; 20956790; 22029951; 22591750; 22612257; 23020937; 26645390; 28331464; 30415926; 30643928; 30870728; 30928199; 31487502Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCN2A variants in ClinVar

67 Conditions Cataloged
Developmental and epileptic encephalopathy, 11Total: 2005
Seizures, benign familial infantile, 3Total: 1899
not providedTotal: 1070
Inborn genetic diseasesTotal: 309
not specifiedTotal: 193
Complex neurodevelopmental disorderTotal: 120
SCN2A-related disorderTotal: 110
Episodic ataxia, type 9Total: 73

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001040142.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
23
clinvar
524
clinvar
14
clinvar
 562
missense
140
clinvar
325
clinvar
1146
clinvar
71
clinvar
5
clinvar
 1687
nonsense
64
clinvar
23
clinvar
4
clinvar
 91
start loss
1
clinvar
1
clinvar
 2
frameshift
105
clinvar
27
clinvar
7
clinvar
 139
splice donor/acceptor (+/-2bp)
24
clinvar
22
clinvar
1
clinvar
 47
Total3343991181595192528

Highest pathogenic variant AF is 0.00002395049

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001040142.2RefSeqNP_001035232.126MANE Select
ENST00000375437.7EnsemblENSP00000364586.226MANE Select
NM_001040143.2RefSeqNP_001035233.126Standard
NM_001371246.1RefSeqNP_001358175.126MANE Plus Clinical

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Taste transduction - Homo sapiens (human)
  • Developmental Biology
  • Phase 0 - rapid depolarisation
  • Cardiac conduction
  • Muscle contraction

Biological Process

  • sodium ion transport
  • intrinsic apoptotic signaling pathway in response to osmotic stress
  • neuronal action potential
  • regulation of ion transmembrane transport
  • sodium ion transmembrane transport

Molecular Function

  • voltage-gated ion channel activity
  • voltage-gated sodium channel activity

Cellular Component

  • voltage-gated sodium channel complex
  • plasma membrane
  • integral component of plasma membrane
  • intercalated disc
  • T-tubule

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000357398
Coding exons
26
Length
152907
Individuals with no LoFs
125727
Homozygous LoFs
0
Heterozygous LoFs
4
Defined
125731
p
0.0000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense6.464691.06e+30.4420.000057213382
Missense (PolyPhen)126481.110.26196144
Synonymous-0.1273743711.010.00002053708
Loss of Function7.92582.70.06050.000004681036

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.00000880.0000088rare
South Asian00.0absent
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
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. {ECO:0000269|PubMed:1325650, ECO:0000269|PubMed:17021166, ECO:0000269|PubMed:28256214}.;
Disease
DISEASE: Seizures, benign familial infantile, 3 (BFIS3) [MIM:607745]: A form of benign familial infantile epilepsy, a neurologic disorder characterized by afebrile seizures occurring in clusters during the first year of life, without neurologic sequelae. BFIS3 inheritance is autosomal dominant. {ECO:0000269|PubMed:11371648, ECO:0000269|PubMed:12243921, ECO:0000269|PubMed:15048894, ECO:0000269|PubMed:16417554, ECO:0000269|PubMed:17021166, ECO:0000269|PubMed:17386050, ECO:0000269|PubMed:18479388, ECO:0000269|PubMed:20371507, ECO:0000269|PubMed:22612257, ECO:0000269|PubMed:23360469, ECO:0000269|PubMed:23758435, ECO:0000269|PubMed:25982755, ECO:0000269|PubMed:26291284}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 11 (EIEE11) [MIM:613721]: An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. {ECO:0000269|PubMed:19783390, ECO:0000269|PubMed:19786696, ECO:0000269|PubMed:20956790, ECO:0000269|PubMed:22677033, ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23195492, ECO:0000269|PubMed:23550958, ECO:0000269|PubMed:23662938, ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:23935176, ECO:0000269|PubMed:23988467, ECO:0000269|PubMed:24463883, ECO:0000269|PubMed:24579881, ECO:0000269|PubMed:24659627, ECO:0000269|PubMed:24710820, ECO:0000269|PubMed:25457084, ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:26138355, ECO:0000269|PubMed:26291284, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in SCN2A are associated with autism spectrum disorders (ASD). It seems that mutations resulting in sodium channel gain of function and increased neuron excitability lead to infantile seizures, whereas variants resulting in sodium channel loss of function and decrease neruon excitability are associated with ASD. {ECO:0000269|PubMed:28256214}.;

Recessive Scores

pRec
0.344

Intolerance Scores

LoFtool
0.00145
RVIS EVS
-1.99
RVIS percentile EVS
1.77

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.710

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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