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
Phenotypes
GenCC
Source:
- 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:
| 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
- 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.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 16 | 493 | 515 | |||
| missense | 76 | 228 | 907 | 75 | 1292 | |
| nonsense | 14 | 13 | 10 | 38 | ||
| start loss | 0 | |||||
| frameshift | 26 | 17 | 14 | 57 | ||
| splice donor/acceptor (+/-2bp) | 17 | |||||
| Total | 122 | 265 | 950 | 570 | 12 |
Highest pathogenic variant AF is 0.00000889377
Loading clinvar variants...
GnomAD
Source:
| 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:
- 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