SCN11A

sodium voltage-gated channel alpha subunit 11, the group of Sodium voltage-gated channel alpha subunits

Basic information

Region (hg38): 3:38845763-39052157

Previous symbols: [ "SCN12A" ]

Links

ENSG00000168356 ∙ NCBI:11280 ∙ OMIM:604385 ∙ HGNC:10583 ∙ Uniprot:Q9UI33 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• sodium channelopathy-related small fiber neuropathy (Supportive), mode of inheritance: AD
• familial episodic pain syndrome with predominantly lower limb involvement (Supportive), mode of inheritance: AD
• hereditary sensory and autonomic neuropathy type 7 (Supportive), mode of inheritance: AD
• familial episodic pain syndrome with predominantly lower limb involvement (Definitive), mode of inheritance: AD
• familial episodic pain syndrome with predominantly lower limb involvement (Strong), mode of inheritance: AD
• hereditary sensory and autonomic neuropathy type 7 (Strong), mode of inheritance: AD
• autosomal dominant hereditary sensory and autonomic neuropathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Episodic pain syndrome, familial, 3; Neuropathy, hereditary sensory and autonomic, type VII	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	24036948; 24207120; 24776970; 25118027
The pain has been reported as responsive to oral anti-inflammatory analgesics; Congenital insensitivity to pain can result in injuries and infections

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SCN11A gene.

• Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement (749 variants)
• not provided (263 variants)
• Inborn genetic diseases (249 variants)
• Familial episodic pain syndrome with predominantly lower limb involvement;Hereditary sensory and autonomic neuropathy type 7 (198 variants)
• not specified (21 variants)
• Hereditary sensory and autonomic neuropathy type 7 (15 variants)
• Familial episodic pain syndrome with predominantly lower limb involvement (14 variants)
• Charcot-Marie-Tooth disease (6 variants)
• SCN11A-related condition (2 variants)
• See cases (1 variants)
• Congenital sensory neuropathy with selective loss of small myelinated fibers (1 variants)
• Sensory neuropathy (1 variants)
• Hereditary motor neuron disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SCN11A 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			10	197	15	222
missense	4	2	550	45	4	605
nonsense		1	26			27
start loss						0
frameshift			30			30
inframe indel			14			14
splice donor/acceptor (+/-2bp)			16			16
splice region			19	23	1	43
non coding			1	108	72	181
Total	4	3	647	350	91

Highest pathogenic variant AF is 0.0000131

Variants in SCN11A

This is a list of pathogenic ClinVar variants found in the SCN11A region.

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

Position	Type	Phenotype	Significance	ClinVar
3-38846479-T-A			Benign (Jul 05, 2018)
3-38846530-T-C			Benign (Jul 05, 2018)
3-38846594-G-T			Likely benign (Sep 22, 2018)
3-38846699-C-G		Familial episodic pain syndrome with predominantly lower limb involvement;Hereditary sensory and autonomic neuropathy type 7	Uncertain significance (Nov 01, 2023)
3-38846702-A-G		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement	Uncertain significance (Oct 13, 2023)
3-38846704-T-C		Familial episodic pain syndrome with predominantly lower limb involvement;Hereditary sensory and autonomic neuropathy type 7 • Inborn genetic diseases	Uncertain significance (Jan 17, 2024)
3-38846711-T-C		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement • Inborn genetic diseases	Conflicting classifications of pathogenicity (Sep 06, 2023)
3-38846712-G-A		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement	Uncertain significance (Mar 25, 2020)
3-38846713-C-T		Inborn genetic diseases	Uncertain significance (Sep 01, 2022)
3-38846724-C-T		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement	Likely benign (Aug 23, 2021)
3-38846729-A-T		Familial episodic pain syndrome with predominantly lower limb involvement;Hereditary sensory and autonomic neuropathy type 7	Uncertain significance (Jul 16, 2023)
3-38846736-C-T		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement	Benign (Feb 01, 2024)
3-38846744-C-G		Familial episodic pain syndrome with predominantly lower limb involvement;Hereditary sensory and autonomic neuropathy type 7	Uncertain significance (Nov 17, 2023)
3-38846749-CAA-C		Familial episodic pain syndrome with predominantly lower limb involvement;Hereditary sensory and autonomic neuropathy type 7	Uncertain significance (May 30, 2023)
3-38846750-A-G		Familial episodic pain syndrome with predominantly lower limb involvement;Hereditary sensory and autonomic neuropathy type 7	Uncertain significance (Dec 30, 2023)
3-38846758-T-C		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement • Inborn genetic diseases	Uncertain significance (Oct 28, 2022)
3-38846759-G-A		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement	Uncertain significance (Nov 04, 2022)
3-38846761-A-G		Familial episodic pain syndrome with predominantly lower limb involvement;Hereditary sensory and autonomic neuropathy type 7	Uncertain significance (Apr 05, 2023)
3-38846764-G-A		Familial episodic pain syndrome with predominantly lower limb involvement;Hereditary sensory and autonomic neuropathy type 7	Uncertain significance (Oct 23, 2023)
3-38846771-G-A		Inborn genetic diseases	Uncertain significance (Jun 06, 2023)
3-38846778-G-A		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement	Likely benign (Nov 03, 2020)
3-38846788-T-C		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement	Uncertain significance (Aug 28, 2022)
3-38846788-T-G		Familial episodic pain syndrome with predominantly lower limb involvement;Hereditary sensory and autonomic neuropathy type 7	Uncertain significance (Nov 03, 2022)
3-38846790-A-T		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement • Inborn genetic diseases	Benign/Likely benign (Dec 15, 2023)
3-38846791-T-C		Hereditary sensory and autonomic neuropathy type 7;Familial episodic pain syndrome with predominantly lower limb involvement	Uncertain significance (May 18, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SCN11A	protein_coding	protein_coding	ENST00000302328	26	104793

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.93e-26	0.961	125517	0	231	125748	0.000919

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.964	881	965	0.913	0.0000517	11927
Missense in Polyphen		324	422.06	0.76765		5339
Synonymous	-0.249	350	344	1.02	0.0000186	3317
Loss of Function	2.84	53	80.5	0.659	0.00000451	933

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00264	0.00264
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.000389	0.000381
Finnish	0.000601	0.000601
European (Non-Finnish)	0.00109	0.000976
Middle Eastern	0.000389	0.000381
South Asian	0.000851	0.000588
Other	0.00117	0.00114

dbNSFP

Source: dbNSFP

• Function: FUNCTION: This protein 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 sodium ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant sodium channel isoform. Also involved, with the contribution of the receptor tyrosine kinase NTRK2, in rapid BDNF-evoked neuronal depolarization. {ECO:0000269|PubMed:10580103, ECO:0000269|PubMed:12384689}.
• Disease: DISEASE: Neuropathy, hereditary sensory and autonomic, 7 (HSAN7) [MIM:615548]: A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN7 is characterized by congenital inability to experience pain resulting in self-mutilations, slow-healing wounds, and multiple painless fractures. mild muscle weakness, delayed motor development, slightly reduced motor and sensory nerve conduction velocities, hyperhidrosis and gastrointestinal dysfunction. {ECO:0000269|PubMed:24036948, ECO:0000269|PubMed:26645915}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Episodic pain syndrome, familial, 3 (FEPS3) [MIM:615552]: An autosomal dominant neurologic disorder characterized by paroxysmal pain mainly affecting the distal lower extremities and occasionally the upper body, especially the joints of fingers and arms. The pain is exacerbated with fatigue. {ECO:0000269|PubMed:24207120, ECO:0000269|PubMed:24776970, ECO:0000269|PubMed:25791876, ECO:0000269|PubMed:27224030}. 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)

Intolerance Scores

• loftool: 0.0774
• rvis_EVS: -1.82
• rvis_percentile_EVS: 2.14

Haploinsufficiency Scores

• pHI: 0.0474
• hipred: N
• hipred_score: 0.233
• ghis: 0.409

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.135

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Scn11a
• 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Gene ontology

• Biological process: sodium ion transport;neuronal action potential;regulation of ion transmembrane transport;sodium ion transmembrane transport;response to drug;regulation of sensory perception of pain;membrane depolarization during action potential
• Cellular component: voltage-gated sodium channel complex;plasma membrane;axon;C-fiber;extracellular exosome
• Molecular function: voltage-gated ion channel activity;voltage-gated sodium channel activity