SCN9A

sodium voltage-gated channel alpha subunit 9, the group of Sodium voltage-gated channel alpha subunits

Basic information

Region (hg38): 2:166195184-166376001

Links

ENSG00000169432 ∙ NCBI:6335 ∙ OMIM:603415 ∙ HGNC:10597 ∙ Uniprot:Q15858 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• channelopathy-associated congenital insensitivity to pain, autosomal recessive (Strong), mode of inheritance: AR
• hereditary sensory and autonomic neuropathy type 2 (Supportive), mode of inheritance: AR
• paroxysmal extreme pain disorder (Supportive), mode of inheritance: AD
• channelopathy-associated congenital insensitivity to pain, autosomal recessive (Supportive), mode of inheritance: AD
• primary erythermalgia (Supportive), mode of inheritance: AD
• sodium channelopathy-related small fiber neuropathy (Supportive), mode of inheritance: AD
• channelopathy-associated congenital insensitivity to pain, autosomal recessive (Strong), mode of inheritance: AR
• primary erythermalgia (Definitive), mode of inheritance: AD
• generalized epilepsy with febrile seizures plus, type 7 (Strong), mode of inheritance: AD
• paroxysmal extreme pain disorder (Strong), mode of inheritance: AD
• epilepsy (Refuted Evidence), mode of inheritance: AD
• primary erythermalgia (Strong), mode of inheritance: AD
• generalized epilepsy with febrile seizures plus, type 7 (Limited), mode of inheritance: AD
• channelopathy-associated congenital insensitivity to pain, autosomal recessive (Limited), mode of inheritance: Semidominant
• epilepsy (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Paroxysmal extreme pain disorder	AD/AR	Neurologic	In Primary erythermalgia, medical treatment (with specific sodium channel blocking agents such as XEN402) has been reported as beneficial; Individuals with Paroxysmal extreme pain disorder have been reported as responding to medical therapy (eg, carbamazepine) in terms of clinical manifestations (attacks of pain) as well as psychomotor development in some	Dermatologic; Neurologic	13636703; 4111621; 4112340; 1536168; 10724194; 14985375; 15958509; 16216943; 17167479; 17145499; 17679678; 17470132; 19304393; 19763161; 21441906; 21698661; 22035805; 23596073; 24817410
Many treatments have been attempted (with inconsistent success) in Erythermalgia, primary, and some have been described by patients as providing subjective relief from symptoms; Indifference to pain, congenital, can result in injuries, some of which may in theory be preventable with early diagnosis and preventive measures

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SCN9A gene.

• Neuropathy, hereditary sensory and autonomic, type 2A;Generalized epilepsy with febrile seizures plus, type 7 (44 variants)
• Generalized epilepsy with febrile seizures plus, type 7;Neuropathy, hereditary sensory and autonomic, type 2A (33 variants)
• not provided (12 variants)
• Channelopathy-associated congenital insensitivity to pain, autosomal recessive (8 variants)
• Primary erythromelalgia (5 variants)
• Inborn genetic diseases (4 variants)
• Paroxysmal extreme pain disorder (3 variants)
• SCN9A-related peripheral neuropathies associated with increased pain (1 variants)
• not specified (1 variants)
• Abnormality of pain sensation;Acute episodes of neuropathic symptoms (1 variants)
• Generalized epilepsy with febrile seizures plus, type 7 (1 variants)
• Pain insensitivity (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SCN9A 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	457	12	480
missense	9	12	1329	38	2	1390
nonsense	34	6	6			46
start loss						0
frameshift	41	7	11			59
inframe indel		1	18			19
splice donor/acceptor (+/-2bp)	4	21	4			29
splice region			45	48	5	98
non coding			45	177	36	258
Total	88	47	1424	672	50

Highest pathogenic variant AF is 0.0000197

Variants in SCN9A

This is a list of pathogenic ClinVar variants found in the SCN9A region.

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

Position	Type	Phenotype	Significance	ClinVar
2-166195246-T-A		Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder • Primary erythromelalgia • Inherited Erythromelalgia	Conflicting classifications of pathogenicity (Jan 13, 2018)
2-166195355-T-C		Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Inherited Erythromelalgia • Primary erythromelalgia	Benign/Likely benign (Jan 13, 2018)
2-166195390-T-G		Small fiber neuropathy • Primary erythromelalgia • Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive	Uncertain significance (Jan 12, 2018)
2-166195468-C-T		Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Primary erythromelalgia • Paroxysmal extreme pain disorder	Uncertain significance (Jan 13, 2018)
2-166195470-A-G		Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder	Uncertain significance (Jan 12, 2018)
2-166195570-G-A		Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Inherited Erythromelalgia • Primary erythromelalgia	Conflicting classifications of pathogenicity (Jan 13, 2018)
2-166195578-T-C		Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder	Uncertain significance (Mar 30, 2018)
2-166195619-C-T		Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Primary erythromelalgia • Paroxysmal extreme pain disorder	Uncertain significance (Jan 13, 2018)
2-166195634-G-A		Primary erythromelalgia • Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Inherited Erythromelalgia	Benign/Likely benign (Jan 12, 2018)
2-166195686-A-C		Primary erythromelalgia • Paroxysmal extreme pain disorder • Inherited Erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive	Uncertain significance (Jan 13, 2018)
2-166195727-G-T		Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Primary erythromelalgia	Uncertain significance (Jan 13, 2018)
2-166195744-C-T		Paroxysmal extreme pain disorder • Inherited Erythromelalgia • Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive	Uncertain significance (Jan 13, 2018)
2-166195812-G-A		Small fiber neuropathy • Paroxysmal extreme pain disorder • Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive	Uncertain significance (Jan 13, 2018)
2-166195818-A-G		Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Inherited Erythromelalgia • Primary erythromelalgia	Benign (Jan 12, 2018)
2-166195927-AG-A		Small fiber neuropathy • Febrile seizures, familial • Congenital Indifference to Pain • Paroxysmal extreme pain disorder • Inherited Erythromelalgia • Generalized epilepsy with febrile seizures plus • Severe myoclonic epilepsy in infancy	Uncertain significance (Jun 14, 2016)
2-166195943-G-T		Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder • Primary erythromelalgia	Uncertain significance (Jan 13, 2018)
2-166195951-G-C		Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder • Primary erythromelalgia • Small fiber neuropathy	Benign/Likely benign (Jan 13, 2018)
2-166195995-A-G		Paroxysmal extreme pain disorder • Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive	Uncertain significance (Jan 13, 2018)
2-166196010-C-T		Paroxysmal extreme pain disorder • Inherited Erythromelalgia • Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive	Benign/Likely benign (Jan 13, 2018)
2-166196032-C-T		Small fiber neuropathy • Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Primary erythromelalgia	Benign (Jan 13, 2018)
2-166196045-CTTAAAAAAGTT-C		Severe myoclonic epilepsy in infancy • Generalized epilepsy with febrile seizures plus • Febrile seizures, familial • Paroxysmal extreme pain disorder • Small fiber neuropathy • Inherited Erythromelalgia • Congenital Indifference to Pain	Benign (Jun 14, 2016)
2-166196132-G-A		Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Small fiber neuropathy • Paroxysmal extreme pain disorder	Benign (Jan 13, 2018)
2-166196328-G-A		Inherited Erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Primary erythromelalgia • Paroxysmal extreme pain disorder	Conflicting classifications of pathogenicity (Jan 13, 2018)
2-166196349-C-A		Primary erythromelalgia • Small fiber neuropathy • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder	Benign/Likely benign (Jan 13, 2018)
2-166196360-T-A		Paroxysmal extreme pain disorder • Inherited Erythromelalgia • Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive	Benign/Likely benign (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SCN9A	protein_coding	protein_coding	ENST00000409672	26	180809

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.75e-19	1.00	125635	0	113	125748	0.000449

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.06	913	1.01e+3	0.906	0.0000524	13101
Missense in Polyphen		343	453.44	0.75643		6036
Synonymous	-1.08	377	351	1.07	0.0000183	3627
Loss of Function	3.70	43	78.3	0.549	0.00000424	1050

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00149	0.00146
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.00154	0.00152
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.000371	0.000360
Middle Eastern	0.00154	0.00152
South Asian	0.000202	0.000196
Other	0.000332	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, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784). {ECO:0000269|PubMed:15178348, ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:16988069, ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:17167479, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784, ECO:0000269|PubMed:25240195, ECO:0000269|PubMed:26680203, ECO:0000269|PubMed:7720699}.
• Disease: DISEASE: Primary erythermalgia (PERYTHM) [MIM:133020]: Autosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands. {ECO:0000269|PubMed:14985375, ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:15955112, ECO:0000269|PubMed:15958509, ECO:0000269|PubMed:16216943, ECO:0000269|PubMed:16392115, ECO:0000269|PubMed:16702558, ECO:0000269|PubMed:16988069, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Indifference to pain, congenital, autosomal recessive (CIP) [MIM:243000]: A disorder characterized by congenital inability to perceive any form of pain, in any part of the body. All other sensory modalities are preserved and the peripheral and central nervous systems are apparently intact. Patients perceive the sensations of touch, warm and cold temperature, proprioception, tickle and pressure, but not painful stimuli. There is no evidence of a motor or sensory neuropathy, either axonal or demyelinating. {ECO:0000269|PubMed:20635406}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Paroxysmal extreme pain disorder (PEPD) [MIM:167400]: Autosomal dominant paroxysmal disorder of pain and autonomic dysfunction. The distinctive features are paroxysmal episodes of burning pain in the rectal, ocular, and mandibular areas accompanied by autonomic manifestations such as skin flushing. {ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:25285947}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Generalized epilepsy with febrile seizures plus 7 (GEFS+7) [MIM:613863]: A rare autosomal dominant, familial condition with incomplete penetrance and large intrafamilial variability. Patients display febrile seizures persisting sometimes beyond the age of 6 years and/or a variety of afebrile seizure types. This disease combines febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, and partial seizures, with a variable degree of severity. {ECO:0000269|PubMed:19763161}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Febrile seizures, familial, 3B (FEB3B) [MIM:613863]: Seizures associated with febrile episodes in childhood without any evidence of intracranial infection or defined pathologic or traumatic cause. It is a common condition, affecting 2-5% of children aged 3 months to 5 years. The majority are simple febrile seizures (generally defined as generalized onset, single seizures with a duration of less than 30 minutes). Complex febrile seizures are characterized by focal onset, duration greater than 30 minutes, and/or more than one seizure in a 24 hour period. The likelihood of developing epilepsy following simple febrile seizures is low. Complex febrile seizures are associated with a moderately increased incidence of epilepsy. {ECO:0000269|PubMed:19763161}. 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: 0.199

Intolerance Scores

• loftool: 0.0121
• rvis_EVS: 0.33
• rvis_percentile_EVS: 73.63

Haploinsufficiency Scores

• pHI: 0.324
• hipred: N
• hipred_score: 0.422
• ghis: 0.464

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.179

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Scn9a
• Phenotype: immune system phenotype; renal/urinary system 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); 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; 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); growth/size/body region phenotype; taste/olfaction phenotype

Gene ontology

• Biological process: sodium ion transport;inflammatory response;response to toxic substance;post-embryonic development;neuronal action potential;sensory perception of pain;regulation of ion transmembrane transport;sodium ion transmembrane transport;behavioral response to pain;membrane depolarization during action potential
• Cellular component: voltage-gated sodium channel complex;plasma membrane;integral component of plasma membrane;axon
• Molecular function: voltage-gated ion channel activity;voltage-gated sodium channel activity;sodium ion binding