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GeneBe

SCN8A

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

Basic information

Region (hg38): 12:51590265-51812864

Previous symbols: [ "MED" ]

Links

ENSG00000196876NCBI:6334OMIM:600702HGNC:10596Uniprot:Q9UQD0AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • cognitive impairment with or without cerebellar ataxia (Definitive), mode of inheritance: AD
  • developmental and epileptic encephalopathy, 13 (Definitive), mode of inheritance: AD
  • benign familial infantile epilepsy (Supportive), mode of inheritance: AD
  • infantile convulsions and choreoathetosis (Supportive), mode of inheritance: AD
  • undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
  • cognitive impairment with or without cerebellar ataxia (Strong), mode of inheritance: AD
  • developmental and epileptic encephalopathy, 13 (Definitive), mode of inheritance: AD
  • myoclonus, familial, 2 (Limited), mode of inheritance: AD
  • complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
  • seizures, benign familial infantile, 5 (Strong), mode of inheritance: AD
  • developmental and epileptic encephalopathy, 13 (Strong), mode of inheritance: AD
  • cognitive impairment with or without cerebellar ataxia (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Developmental and epileptic encephalopathy 13; Seizures, benign familial infantile, 5ADNeurologicIndividuals may manifest with seizures, and specific knowledge of the underlying cause can help direct selection of optimal therapies for management based on the genetic etiologyNeurologic; Ophthalmologic16236810; 22365152; 24888894; 25239001; 26677014; 27210545; 28331464; 29726066; 31026061; 31402610
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SCN8A gene.

  • Early infantile epileptic encephalopathy with suppression bursts (1311 variants)
  • not provided (575 variants)
  • Inborn genetic diseases (158 variants)
  • Developmental and epileptic encephalopathy, 13 (147 variants)
  • not specified (116 variants)
  • Cognitive impairment with or without cerebellar ataxia (62 variants)
  • Seizures, benign familial infantile, 5 (31 variants)
  • SCN8A-related condition (20 variants)
  • Myoclonus, familial, 2 (13 variants)
  • Early Infantile Epileptic Encephalopathy, Autosomal Dominant (9 variants)
  • See cases (7 variants)
  • Neurodevelopmental disorder (7 variants)
  • Epileptic encephalopathy (7 variants)
  • Seizure (6 variants)
  • SCN8A-related disorder (4 variants)
  • Cognitive impairment with or without cerebellar ataxia;Seizures, benign familial infantile, 5;Developmental and epileptic encephalopathy, 13 (3 variants)
  • Seizures, benign familial infantile, 5;Cognitive impairment with or without cerebellar ataxia;Developmental and epileptic encephalopathy, 13 (3 variants)
  • Global developmental delay;Autosomal recessive inheritance;Seizure (3 variants)
  • Developmental and epileptic encephalopathy, 13;Seizures, benign familial infantile, 5;Myoclonus, familial, 2;Cognitive impairment with or without cerebellar ataxia (2 variants)
  • Intellectual disability (2 variants)
  • Global developmental delay;Seizure (2 variants)
  • Cognitive impairment with or without cerebellar ataxia;Developmental and epileptic encephalopathy, 13;Seizures, benign familial infantile, 5 (2 variants)
  • Seizures, benign familial infantile, 5;Developmental and epileptic encephalopathy, 13 (2 variants)
  • Cognitive impairment with or without cerebellar ataxia;Myoclonus, familial, 2;Developmental and epileptic encephalopathy, 13;Seizures, benign familial infantile, 5 (2 variants)
  • Developmental and epileptic encephalopathy, 13;Seizures, benign familial infantile, 5;Cognitive impairment with or without cerebellar ataxia (2 variants)
  • Epilepsy (2 variants)
  • Developmental and epileptic encephalopathy, 13;Myoclonus, familial, 2;Seizures, benign familial infantile, 5;Cognitive impairment with or without cerebellar ataxia (2 variants)
  • Developmental and epileptic encephalopathy, 13;Seizures, benign familial infantile, 5 (2 variants)
  • SCN8A-related complex neurodevelopmental disorder (2 variants)
  • Cognitive impairment with or without cerebellar ataxia;Developmental and epileptic encephalopathy, 13 (2 variants)
  • Developmental and epileptic encephalopathy, 13;Cognitive impairment with or without cerebellar ataxia;Seizures, benign familial infantile, 5 (2 variants)
  • COGNITIVE IMPAIRMENT WITHOUT CEREBELLAR ATAXIA (2 variants)
  • Seizure;Intellectual disability (2 variants)
  • Seizures, benign familial infantile, 5;Myoclonus, familial, 2;Cognitive impairment with or without cerebellar ataxia;Developmental and epileptic encephalopathy, 13 (2 variants)
  • Developmental and epileptic encephalopathy, 13;Cognitive impairment with or without cerebellar ataxia;Myoclonus, familial, 2;Seizures, benign familial infantile, 5 (1 variants)
  • Abnormal cerebral morphology (1 variants)
  • Seizures, benign familial infantile, 5;Developmental and epileptic encephalopathy, 13;Cognitive impairment with or without cerebellar ataxia (1 variants)
  • Arthrogryposis multiplex congenita;Fetal akinesia deformation sequence 1 (1 variants)
  • Seizure;Global developmental delay;Autosomal recessive inheritance (1 variants)
  • Global developmental delay;Choreoathetosis;Leukoencephalopathy;Febrile seizure (within the age range of 3 months to 6 years) (1 variants)
  • Cerebellar ataxia;Intellectual disability (1 variants)
  • Myoclonus, familial, 2;Seizures, benign familial infantile, 5;Cognitive impairment with or without cerebellar ataxia;Developmental and epileptic encephalopathy, 13 (1 variants)
  • SUDDEN INFANT DEATH SYNDROME (1 variants)
  • SCN8A-related epileptic disorder (1 variants)
  • Autism;Seizure;Intellectual disability (1 variants)
  • Developmental and epileptic encephalopathy, 64 (1 variants)
  • Seizures, benign familial infantile, 5;Cognitive impairment with or without cerebellar ataxia;Myoclonus, familial, 2;Developmental and epileptic encephalopathy, 13 (1 variants)
  • Cognitive impairment with or without cerebellar ataxia;Seizures, benign familial infantile, 5;Myoclonus, familial, 2;Developmental and epileptic encephalopathy, 13 (1 variants)
  • Intellectual disability, moderate (1 variants)
  • Spastic ataxia (1 variants)
  • Focal impaired awareness seizure (1 variants)
  • developmental delay with seizures (1 variants)
  • SCN8A-related disorders (1 variants)
  • Focal epilepsy (1 variants)
  • Developmental and epileptic encephalopathy, 13;Cognitive impairment with or without cerebellar ataxia;Seizures, benign familial infantile, 5;Myoclonus, familial, 2 (1 variants)
  • West syndrome (1 variants)
  • 6 conditions (1 variants)
  • Bilateral tonic-clonic seizure (1 variants)
  • Developmental and epileptic encephalopathy, 1 (1 variants)
  • Focal clonic seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SCN8A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
16
clinvar
377
clinvar
11
clinvar
404
missense
49
clinvar
126
clinvar
683
clinvar
36
clinvar
3
clinvar
897
nonsense
9
clinvar
7
clinvar
15
clinvar
31
start loss
0
frameshift
11
clinvar
11
clinvar
13
clinvar
35
inframe indel
1
clinvar
17
clinvar
18
splice donor/acceptor (+/-2bp)
3
clinvar
8
clinvar
3
clinvar
1
clinvar
15
splice region
1
29
45
4
79
non coding
15
clinvar
160
clinvar
58
clinvar
233
Total 72 153 762 574 72

Highest pathogenic variant AF is 0.00000657

Variants in SCN8A

This is a list of pathogenic ClinVar variants found in the SCN8A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
12-51591343-TCGC-T SCN8A-related condition Likely benign (Apr 19, 2021)3029905
12-51591347-C-T not specified • SCN8A-related condition Benign/Likely benign (Aug 18, 2022)207103
12-51591353-C-T not specified Likely benign (Dec 07, 2016)379153
12-51591371-C-T Benign (Mar 03, 2015)1266367
12-51591372-A-G not specified Likely benign (Feb 08, 2018)509397
12-51591379-C-G not specified Likely benign (Dec 01, 2015)381890
12-51662760-C-G Likely benign (Feb 11, 2021)1210841
12-51662821-G-A Early infantile epileptic encephalopathy with suppression bursts Uncertain significance (May 28, 2021)1508927
12-51662825-C-T Early infantile epileptic encephalopathy with suppression bursts • Inborn genetic diseases Uncertain significance (Aug 24, 2023)461351
12-51662826-G-A Early infantile epileptic encephalopathy with suppression bursts Likely benign (May 15, 2023)1584325
12-51662827-C-T Early infantile epileptic encephalopathy with suppression bursts Uncertain significance (Sep 18, 2023)1020681
12-51662828-G-A Early infantile epileptic encephalopathy with suppression bursts Uncertain significance (Jun 20, 2022)449257
12-51662832-G-C Early infantile epileptic encephalopathy with suppression bursts Likely benign (Jul 05, 2022)1124235
12-51662836-G-C Uncertain significance (Oct 16, 2019)1318212
12-51662838-A-C Uncertain significance (Oct 21, 2020)1317384
12-51662848-C-A Early infantile epileptic encephalopathy with suppression bursts Likely benign (Jan 07, 2020)964512
12-51662852-A-G Inborn genetic diseases Uncertain significance (May 26, 2017)589120
12-51662853-T-C Early infantile epileptic encephalopathy with suppression bursts Likely benign (Sep 30, 2021)1588798
12-51662853-T-G Early infantile epileptic encephalopathy with suppression bursts Uncertain significance (Jul 12, 2022)1064214
12-51662860-A-C Coffin-Siris syndrome 8 Uncertain significance (Nov 04, 2022)2431746
12-51662864-C-T Early infantile epileptic encephalopathy with suppression bursts Uncertain significance (Feb 04, 2022)850466
12-51662865-T-C Early infantile epileptic encephalopathy with suppression bursts Likely benign (Jun 10, 2022)1971014
12-51662866-TTCACCC-T Early infantile epileptic encephalopathy with suppression bursts Uncertain significance (Oct 01, 2022)1063414
12-51662868-C-G Early infantile epileptic encephalopathy with suppression bursts Uncertain significance (May 07, 2019)641963
12-51662872-CCT-C Likely pathogenic (Aug 01, 2019)871342

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
SCN8Aprotein_codingprotein_codingENST00000354534 26222599
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
1.005.30e-10125146071251530.0000280
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense7.643911.11e+30.3540.000061513183
Missense in Polyphen115562.210.204556828
Synonymous1.613784200.9000.00002423716
Loss of Function7.81580.70.06200.00000452969

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.000.00
Ashkenazi Jewish0.000.00
East Asian0.000.00
Finnish0.000.00
European (Non-Finnish)0.00006510.0000617
Middle Eastern0.000.00
South Asian0.000.00
Other0.000.00

dbNSFP

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.;
Pathway
Developmental Biology;Phase 0 - rapid depolarisation;Cardiac conduction;Muscle contraction;Interaction between L1 and Ankyrins;L1CAM interactions;Axon guidance (Consensus)

Recessive Scores

pRec
0.255

Intolerance Scores

loftool
0.0157
rvis_EVS
-1.75
rvis_percentile_EVS
2.34

Haploinsufficiency Scores

pHI
0.603
hipred
Y
hipred_score
0.681
ghis
0.617

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.702

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Scn8a
Phenotype
cellular phenotype; muscle phenotype; growth/size/body region phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span);

Zebrafish Information Network

Gene name
scn8aa
Affected structure
secondary motor neuron
Phenotype tag
abnormal
Phenotype quality
misrouted

Gene ontology

Biological process
sodium ion transport;nervous system development;peripheral nervous system development;neuronal action potential;regulation of ion transmembrane transport;sodium ion transmembrane transport;myelination;membrane depolarization during action potential
Cellular component
voltage-gated sodium channel complex;plasma membrane;integral component of membrane;Z disc;axon;cytoplasmic vesicle;node of Ranvier;axon initial segment
Molecular function
voltage-gated ion channel activity;voltage-gated sodium channel activity;protein binding;ATP binding