SCN8A

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

Basic information

Region (hg38): 12:51590266-51812864

Previous symbols: [ "MED" ]

Links

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

Phenotypes

GenCC

Source: genCC

  • 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
  • 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
  • complex neurodevelopmental disorder (Definitive), 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.

  • Developmental_and_epileptic_encephalopathy (1639 variants)
  • not_provided (746 variants)
  • Developmental_and_epileptic_encephalopathy,_13 (223 variants)
  • Inborn_genetic_diseases (210 variants)
  • not_specified (130 variants)
  • Cognitive_impairment_with_or_without_cerebellar_ataxia (106 variants)
  • SCN8A-related_disorder (69 variants)
  • Seizures,_benign_familial_infantile,_5 (69 variants)
  • Myoclonus,_familial,_2 (27 variants)
  • Seizure (16 variants)
  • Intellectual_disability (10 variants)
  • Global_developmental_delay (9 variants)
  • See_cases (8 variants)
  • Epileptic_encephalopathy (8 variants)
  • Neurodevelopmental_disorder (7 variants)
  • Complex_neurodevelopmental_disorder (5 variants)
  • Autosomal_recessive_inheritance (4 variants)
  • COGNITIVE_IMPAIRMENT_WITHOUT_CEREBELLAR_ATAXIA (2 variants)
  • Epilepsy (2 variants)
  • SCN8A-related_complex_neurodevelopmental_disorder (2 variants)
  • Autism (2 variants)
  • Focal_clonic_seizure (1 variants)
  • Leukoencephalopathy (1 variants)
  • Focal_epilepsy (1 variants)
  • Generalized_tonic_seizure (1 variants)
  • SCN8A-related_neurodevelopmental_delay (1 variants)
  • SCN8A-related_epileptic_disorder (1 variants)
  • Intellectual_disability,_severe (1 variants)
  • Developmental_and_epileptic_encephalopathy,_1 (1 variants)
  • Intellectual_disability,_moderate (1 variants)
  • Developmental_stagnation_at_onset_of_seizures (1 variants)
  • Bilateral_tonic-clonic_seizure (1 variants)
  • Abnormal_cerebral_morphology (1 variants)
  • West_syndrome (1 variants)
  • Infantile_spasms (1 variants)
  • Hereditary_ataxia (1 variants)
  • Febrile_seizure_(within_the_age_range_of_3_months_to_6_years) (1 variants)
  • Developmental_and_epileptic_encephalopathy,_64 (1 variants)
  • Developmental_regression (1 variants)
  • Arthrogryposis_multiplex_congenita (1 variants)
  • developmental_delay_with_seizures (1 variants)
  • Undetermined_early-onset_epileptic_encephalopathy (1 variants)
  • Myoclonus (1 variants)
  • Early_Infantile_Epileptic_Encephalopathy,_Autosomal_Dominant (1 variants)
  • Cerebellar_ataxia (1 variants)
  • Choreoathetosis (1 variants)
  • Fetal_akinesia_deformation_sequence_1 (1 variants)
  • Spastic_ataxia (1 variants)
  • SUDDEN_INFANT_DEATH_SYNDROME (1 variants)
  • Malaria,_susceptibility_to (1 variants)
  • Developmental_disorder (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. These statistics are base on transcript: NM_001330260.2. Only rare variants are included in the table.

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.

EffectPLPVUSLBBSum
synonymous
16
clinvar
493
clinvar
6
clinvar
515
missense
76
clinvar
228
clinvar
907
clinvar
75
clinvar
6
clinvar
1292
nonsense
14
clinvar
13
clinvar
10
clinvar
1
clinvar
38
start loss
0
frameshift
26
clinvar
17
clinvar
14
clinvar
57
splice donor/acceptor (+/-2bp)
6
clinvar
7
clinvar
3
clinvar
1
clinvar
17
Total 122 265 950 570 12

Highest pathogenic variant AF is 0.00000889377

Loading clinvar variants...

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