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
• 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
• developmental and epileptic encephalopathy (Definitive), 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.

• Early infantile epileptic encephalopathy with suppression bursts (3 variants)
• not provided (3 variants)
• Developmental and epileptic encephalopathy, 62 (2 variants)
• Developmental and epileptic encephalopathy, 62;Epilepsy, familial focal, with variable foci 4 (1 variants)
• Developmental delay;Polymicrogyria (1 variants)
• Inborn genetic diseases (1 variants)
• Epilepsy, familial focal, with variable foci 4 (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.

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			11	376	17	404
missense	2	19	783	53	4	861
nonsense	2		19			21
start loss						0
frameshift	2	2	17			21
inframe indel		1	6		1	8
splice donor/acceptor (+/-2bp)		1	4			5
splice region			27	45	1	73
non coding			7	136	51	194
Total	6	23	847	565	73

Highest pathogenic variant AF is 0.00000657

Variants in SCN3A

This is a list of pathogenic ClinVar variants found in the SCN3A region.

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

Position	Type	Phenotype	Significance	ClinVar
2-165090153-C-T			Likely benign (Dec 20, 2023)
2-165090155-T-C			Uncertain significance (Oct 23, 2019)
2-165090155-T-G			Uncertain significance (Nov 27, 2023)
2-165090156-T-G			Likely benign (Dec 25, 2023)
2-165090157-T-G			Uncertain significance (Dec 06, 2023)
2-165090160-T-C			Uncertain significance (May 06, 2021)
2-165090162-TTC-T			Uncertain significance (Feb 03, 2021)
2-165090164-C-A			Uncertain significance (Jul 25, 2022)
2-165090166-C-G			Uncertain significance (Aug 10, 2022)
2-165090169-A-T			Uncertain significance (Dec 30, 2023)
2-165090170-C-T			Uncertain significance (Jun 30, 2021)
2-165090178-C-A			Uncertain significance (Nov 15, 2022)
2-165090183-G-C			Uncertain significance (Sep 26, 2022)
2-165090185-T-C			Uncertain significance (Sep 27, 2022)
2-165090188-C-T			Uncertain significance (Jan 03, 2024)
2-165090197-G-T		Inborn genetic diseases	Uncertain significance (Apr 26, 2024)
2-165090201-G-A		not specified • SCN3A-related disorder	Benign/Likely benign (Feb 01, 2024)
2-165090204-T-C			Likely benign (Aug 31, 2022)
2-165090206-T-C			Uncertain significance (Aug 09, 2022)
2-165090206-T-G		Developmental and epileptic encephalopathy, 62 • Epilepsy, familial focal, with variable foci 1	Uncertain significance (Jun 22, 2022)
2-165090213-C-T			Likely benign (Sep 01, 2022)
2-165090218-C-T			Uncertain significance (May 27, 2022)
2-165090224-C-G			Uncertain significance (Dec 06, 2021)
2-165090227-G-A			Uncertain significance (Sep 07, 2022)
2-165090227-G-GT			Uncertain significance (Dec 27, 2023)

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