SCN3A

sodium voltage-gated channel alpha subunit 3, the group of Sodium voltage-gated channel alpha subunits

Basic information

Region (hg38): 2:165087526-165204050

Links

ENSG00000153253

∙ NCBI:6328 ∙ OMIM:182391 ∙ HGNC:10590 ∙ Uniprot:Q9NY46 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
genetic developmental and epileptic encephalopathy (Definitive), mode of inheritance: AD
developmental and epileptic encephalopathy, 62 (Strong), mode of inheritance: AD
epilepsy, familial focal, with variable foci 4 (Strong), mode of inheritance: AD
genetic developmental and epileptic encephalopathy (Definitive), mode of inheritance: AD
epilepsy, familial focal, with variable foci 4 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epilepsy, familial focal, with variable foci 4; Developmental and epileptic encephalopathy 62	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	24157691; 29466837
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 SCN3A gene.

not_provided (1823 variants)
Inborn_genetic_diseases (152 variants)
Developmental_and_epileptic_encephalopathy,_62 (74 variants)
Epilepsy,_familial_focal,_with_variable_foci_4 (58 variants)
SCN3A-related_disorder (49 variants)
not_specified (16 variants)
Developmental_and_epileptic_encephalopathy (5 variants)
Seizure (5 variants)
See_cases (3 variants)
Epilepsy (2 variants)
SCN3A-related_neurodevelopmental_disorder (2 variants)
SCN3A-related_neurodevelopmental_sisorder (2 variants)
Neurodevelopmental_disorder (1 variants)
atypical_cerebral_palsy (1 variants)
Congenital_bilateral_perisylvian_syndrome (1 variants)
Epilepsy,_focal,_SCN3A_related (1 variants)
Polymicrogyria (1 variants)
Epilepsy,_idiopathic_generalized,_susceptibility_to,_7 (1 variants)
Developmental_delay (1 variants)
Epilepsy,_familial_focal,_with_variable_foci_1 (1 variants)
Neurodevelopmental_abnormality (1 variants)
Developmental_and_epileptic_encephalopathy,_1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SCN3A gene is commonly pathogenic or not. These statistics are base on transcript: NM_000006922.4. 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			11 clinvar	455 clinvar	15 clinvar	481
missense	3 clinvar	28 clinvar	983 clinvar	87 clinvar	3 clinvar	1104
nonsense	2 clinvar		27 clinvar			29
start loss						0
frameshift	1 clinvar	4 clinvar	23 clinvar			28
splice donor/acceptor (+/-2bp)		3 clinvar	7 clinvar			10
Total	6	35	1051	542	18

Highest pathogenic variant AF is 0.0000218898

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SCN3A	protein_coding	protein_coding	ENST00000283254	26	116546

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	3.05e-8	125728	0	20	125748	0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.62	629	1.05e+3	0.599	0.0000555	13365
Missense in Polyphen		299	563.36	0.53074		7247
Synonymous	-1.24	401	371	1.08	0.0000204	3695
Loss of Function	7.63	8	83.1	0.0963	0.00000476	1032

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000478	0.000416
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.00	0.00
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.0000535	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000163	0.000163

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, forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:24157691, PubMed:28235671, PubMed:29466837). May contribute to the regulation of serotonin/5-hydroxytryptamine release by enterochromaffin cells (By similarity). In pancreatic endocrine cells, required for both glucagon and glucose-induced insulin secretion (By similarity). {ECO:0000250|UniProtKB:A2ASI5, ECO:0000269|PubMed:24157691, ECO:0000269|PubMed:28235671, ECO:0000269|PubMed:29466837}.;
Disease: DISEASE: Epilepsy, familial focal, with variable foci 4 (FFEVF4) [MIM:617935]: An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. Seizure types commonly include temporal lobe epilepsy, frontal lobe epilepsy, and nocturnal frontal lobe epilepsy. Some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. A subset of patients have structural brain abnormalities. Penetrance of the disorder is incomplete. FFEVF4 is characterized by onset of focal seizures in the first years of life. {ECO:0000269|PubMed:24157691, ECO:0000269|PubMed:28235671}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 62 (EIEE62) [MIM:617938]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE62 is characterized by onset of seizures in the first year of life. {ECO:0000269|PubMed:29466837}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Taste transduction - Homo sapiens (human);Developmental Biology;Phase 0 - rapid depolarisation;Cardiac conduction;Muscle contraction;Interaction between L1 and Ankyrins;L1CAM interactions;Axon guidance (Consensus)

Recessive Scores

pRec: 0.106

Intolerance Scores

loftool: 0.00586
rvis_EVS: -2.48
rvis_percentile_EVS: 0.97

Haploinsufficiency Scores

pHI: 0.587
hipred: Y
hipred_score: 0.809
ghis: 0.621

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.881

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Scn3a
Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); normal phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype;

Gene ontology

Biological process: sodium ion transport;neuronal action potential;regulation of ion transmembrane transport;sodium ion transmembrane transport;membrane depolarization during action potential
Cellular component: voltage-gated sodium channel complex;cytoplasm;plasma membrane;axon
Molecular function: voltage-gated ion channel activity;voltage-gated sodium channel activity