SCN7A

protein-coding

sodium voltage-gated channel alpha subunit 7

Gene summary

This gene encodes one of the many voltage-gated sodium channel proteins. For proper functioning of neurons and muscles during action potentials, voltage-gated sodium channels direct sodium ion diffusion for membrane depolarization. This sodium channel protein has some atypical characteristics; the similarity between the human and mouse proteins is lower compared to other orthologous sodium channel pairs. Also, the S4 segments, which sense voltage changes, have fewer positive charged residues that in other sodium channels; domain 4 has fewer arginine and lysine residues compared to other sodium channel proteins. Several alternatively spliced transcript variants exist, but the full-length natures of all of them remain unknown. [provided by RefSeq, Dec 2011]

Previous symbols:

SCN6A

MANE transcript

NM_002976.4

Inheritance

ClinVar variants

P:1U:203B:61

Top phenotype

SCN7A-related disorder

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr2:166,403,573-166,611,482

External References & Databases

Ensembl (ENSG00000136546)

Transcript & Mutation Effects

hg38 • Region Span ~207.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

holoprosencephalyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0016296

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCN7A variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 206

not providedTotal: 57

SCN7A-related disorderTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002976.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				17 clinvar	6 clinvar	23
missense			199 clinvar	25 clinvar	10 clinvar	234
nonsense		1 clinvar	2 clinvar	1 clinvar		4
start loss						0
frameshift			2 clinvar		1 clinvar	3
splice donor/acceptor (+/-2bp)					1 clinvar	1
Total	0	1	203	43	18	265

Highest pathogenic variant AF is 0.00000763504

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002976.4	RefSeq	NP_002967.2	24	MANE Select
ENST00000643258.1	Ensembl	ENSP00000496114.1	24	MANE Select
ENST00000419992.6	Ensembl	ENSP00000413699.2	13	Standard
ENST00000424326.5	Ensembl	ENSP00000396600.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
Developmental Biology
Phase 0 - rapid depolarisation
Cardiac conduction
Muscle contraction

Biological Process

sodium ion transport
muscle contraction
response to bacterium
neuronal action potential
regulation of ion transmembrane transport

Molecular Function

voltage-gated ion channel activity
voltage-gated sodium channel activity

Cellular Component

voltage-gated sodium channel complex
plasma membrane
axon
glial cell projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409855
Coding exons: 24
Length: 90675
Individuals with no LoFs: 125471
Homozygous LoFs: 1
Heterozygous LoFs: 271
Defined: 125743
p: 0.00108

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.407	761	793	0.959	0.0000375	11092
Missense (PolyPhen)		245	273.65	0.89532		4079
Synonymous	-0.590	281	269	1.05	0.0000129	3017
Loss of Function	2.95	37	62.1	0.596	0.00000300	903

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00065	0.00062	rare
Latino/Admixed American	0.00069	0.00067	rare
Ashkenazi Jewish	0.0019	0.0019	notable
East Asian	0.0018	0.0017	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00058	0.00055	rare
South Asian	0.0041	0.0040	notable
Other	0.00086	0.00081	rare

dbNSFP Gene Annotations

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. {ECO:0000305}.;

Recessive Scores

pRec: 0.0940

Intolerance Scores

LoFtool: 0.115
RVIS EVS: 0.86
RVIS percentile EVS: 88.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.189

Gene Damage Prediction

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