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

ENSG00000196876 ∙ NCBI:6334 ∙ OMIM:600702 ∙ HGNC:10596 ∙ Uniprot:Q9UQD0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

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
• 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

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 13; Seizures, benign familial infantile, 5	AD	Neurologic	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	Neurologic; Ophthalmologic	16236810; 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 (47 variants)
• not provided (29 variants)
• Developmental and epileptic encephalopathy, 13 (20 variants)
• Complex neurodevelopmental disorder (12 variants)
• Inborn genetic diseases (11 variants)
• Cognitive impairment with or without cerebellar ataxia (4 variants)
• Seizures, benign familial infantile, 5 (3 variants)
• Epileptic encephalopathy (2 variants)
• Seizures, benign familial infantile, 5;Developmental and epileptic encephalopathy, 13 (1 variants)
• Epilepsy (1 variants)
• Neurodevelopmental disorder (1 variants)
• See cases (1 variants)
• COGNITIVE IMPAIRMENT WITHOUT CEREBELLAR ATAXIA (1 variants)
• Global developmental delay;Seizure (1 variants)
• Seizures, benign familial infantile, 5;Myoclonus, familial, 2;Developmental and epileptic encephalopathy, 13 (1 variants)
• Seizure (1 variants)
• developmental delay with seizures (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	419	9	444
missense	61	137	748	32	5	983
nonsense	12	8	13	1		34
start loss						0
frameshift	15	12	12			39
inframe indel		1	20			21
splice donor/acceptor (+/-2bp)	3	8	3	1		15
splice region		1	31	51	4	87
non coding			17	187	58	262
Total	91	166	829	640	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 disorder	Likely benign (Apr 19, 2021)
12-51591347-C-T		not specified • SCN8A-related disorder	Benign/Likely benign (Aug 18, 2022)
12-51591353-C-T		not specified	Likely benign (Dec 07, 2016)
12-51591371-C-T			Benign (Mar 03, 2015)
12-51591372-A-G		not specified	Likely benign (Feb 08, 2018)
12-51591379-C-G		not specified	Likely benign (Dec 01, 2015)
12-51662760-C-G			Likely benign (Feb 11, 2021)
12-51662821-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (May 28, 2021)
12-51662825-C-T		Early infantile epileptic encephalopathy with suppression bursts • Inborn genetic diseases	Uncertain significance (Aug 24, 2023)
12-51662826-G-A		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (May 15, 2023)
12-51662827-C-T		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Sep 18, 2023)
12-51662828-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Jun 20, 2022)
12-51662832-G-C		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Jul 05, 2022)
12-51662836-G-C			Uncertain significance (Oct 16, 2019)
12-51662838-A-C			Uncertain significance (Oct 21, 2020)
12-51662848-C-A		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Jan 07, 2020)
12-51662852-A-G		Inborn genetic diseases	Uncertain significance (May 26, 2017)
12-51662853-T-C		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Sep 30, 2021)
12-51662853-T-G		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Jul 12, 2022)
12-51662860-A-C		Coffin-Siris syndrome 8	Uncertain significance (Nov 04, 2022)
12-51662864-C-T		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Feb 04, 2022)
12-51662865-T-C		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Jun 10, 2022)
12-51662866-TTCACCC-T		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Oct 01, 2022)
12-51662868-C-G		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (May 07, 2019)
12-51662872-CCT-C			Likely pathogenic (Aug 01, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SCN8A	protein_coding	protein_coding	ENST00000354534	26	222599

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	5.30e-10	125146	0	7	125153	0.0000280

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	7.64	391	1.11e+3	0.354	0.0000615	13183
Missense in Polyphen		115	562.21	0.20455		6828
Synonymous	1.61	378	420	0.900	0.0000242	3716
Loss of Function	7.81	5	80.7	0.0620	0.00000452	969

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000651	0.0000617
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

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

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

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