GeneBe

SCN8A

protein-coding

sodium voltage-gated channel alpha subunit 8, the group of Sodium voltage-gated channel alpha subunits

Gene summary

This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

Previous symbols:
  • MED

MANE transcript

NM_001330260.2

Inheritance

AD, AR

ClinVar variants

P:427U:1050B:617

Top phenotype

Developmental and epileptic encephalopathy 13; Seizures, benign familial infantile, 5

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr12:51,590,266-51,812,864

External References & Databases

Ensembl (ENSG00000196876)NCBI Gene (6334)OMIM (600702)HGNC:10596GenCCUniProt (Q9UQD0)AlphaFoldClinVar (SCN8A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~222.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

seizures, benign familial infantile, 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014903

Submitter: Labcorp Genetics (formerly Invitae)

cognitive impairment with or without cerebellar ataxiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013680

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 13DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013801

Submitter: Ambry Genetics

myoclonus, familial, 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100092

Submitter: Ambry Genetics

cognitive impairment with or without cerebellar ataxiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013680

Submitter: Labcorp Genetics (formerly Invitae)

benign familial infantile epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017615

Submitter: Orphanet

developmental and epileptic encephalopathy, 13LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013801

Submitter: PanelApp Australia

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Approved by the ClinGen Epilepsy Expert Panel 10/20/2017.

developmental and epileptic encephalopathy, 13STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013801

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 13DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013801

Submitter: G2P

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 13; Seizures, benign familial infantile, 5AD

Manifestation: Neurologic; Ophthalmologic

Intervention: Neurologic

Rationale: Individuals may manifest with seizures, and specific knowledge of the underlying cause can help direct selection of optimal therapies for management based on the genetic etiology

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 16236810; 22365152; 24888894; 25239001; 26677014; 27210545; 28331464; 29726066; 31026061; 31402610Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCN8A variants in ClinVar

53 Conditions Cataloged
Early-infantile DEETotal: 1721
not providedTotal: 816
Developmental and epileptic encephalopathy, 13Total: 246
Inborn genetic diseasesTotal: 237
not specifiedTotal: 140
Cognitive impairment with or without cerebellar ataxiaTotal: 120
SCN8A-related disorderTotal: 78
Seizures, benign familial infantile, 5Total: 74

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001330260.2. 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
20
clinvar
522
clinvar
7
clinvar
 549
missense
84
clinvar
249
clinvar
1002
clinvar
78
clinvar
7
clinvar
 1420
nonsense
14
clinvar
15
clinvar
10
clinvar
1
clinvar
 40
start loss
0
frameshift
27
clinvar
20
clinvar
15
clinvar
 62
splice donor/acceptor (+/-2bp)
6
clinvar
12
clinvar
3
clinvar
2
clinvar
 23
Total1312961050603142094

Highest pathogenic variant AF is 0.000008893766

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001330260.2RefSeqNP_001317189.126MANE Select
ENST00000627620.5EnsemblENSP00000487583.226MANE Select
NM_001177984.3RefSeqNP_001171455.125Standard
NM_001369788.1RefSeqNP_001356717.125Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
scn8aaDanio rerio

Structure: secondary motor neuron

Quality: misrouted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Developmental Biology
  • Phase 0 - rapid depolarisation
  • Cardiac conduction
  • Muscle contraction
  • Interaction between L1 and Ankyrins

Biological Process

  • sodium ion transport
  • nervous system development
  • peripheral nervous system development
  • neuronal action potential
  • regulation of ion transmembrane transport

Molecular Function

  • voltage-gated ion channel activity
  • voltage-gated sodium channel activity
  • protein binding
  • ATP binding

Cellular Component

  • voltage-gated sodium channel complex
  • plasma membrane
  • integral component of membrane
  • Z disc
  • axon

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000354534
Coding exons
26
Length
222599
Individuals with no LoFs
125146
Homozygous LoFs
0
Heterozygous LoFs
7
Defined
125153
p
0.0000280
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense7.643911.11e+30.3540.000061513183
Missense (PolyPhen)115562.210.204556828
Synonymous1.613784200.9000.00002423716
Loss of Function7.81580.70.06200.00000452969

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000650.000062rare
South Asian00.0absent
Other00.0absent

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. In macrophages and melanoma cells, isoform 5 may participate in the control of podosome and invadopodia formation. {ECO:0000269|PubMed:19136557}.;
Disease
DISEASE: Cognitive impairment with or without cerebellar ataxia (CIAT) [MIM:614306]: A disorder characterized by markedly delayed cognitive and motor development, attention deficit disorder, and cerebellar ataxia. Features include bilateral esophoria, strabismatic amblyopia, unsustained gaze evoked nystagmus on horizontal gaze, ataxic gait, dysmetria in the upper limbs and dysarthria, with normal strength, tone, and reflexes. {ECO:0000269|PubMed:16236810}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 13 (EIEE13) [MIM:614558]: A form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high- voltage bursts alternating with almost flat suppression phases. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. EIEE13 is a severe form consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. {ECO:0000269|PubMed:22365152, ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:24352161, ECO:0000269|PubMed:24874546, ECO:0000269|PubMed:24888894, ECO:0000269|PubMed:25239001, ECO:0000269|PubMed:25568300, ECO:0000269|PubMed:25725044, ECO:0000269|PubMed:25785782, ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:26900580, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27210545, ECO:0000269|PubMed:27864847, ECO:0000269|PubMed:28923014}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Seizures, benign familial infantile, 5 (BFIS5) [MIM:617080]: 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. BFIS5 inheritance is autosomal dominant. {ECO:0000269|PubMed:26677014, ECO:0000269|PubMed:27210545}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.255

Intolerance Scores

LoFtool
0.0157
RVIS EVS
-1.75
RVIS percentile EVS
2.34

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.702

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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