SCN2A

sodium voltage-gated channel alpha subunit 2, the group of Sodium voltage-gated channel alpha subunits

Basic information

Region (hg38): 2:165194992-165392310

Previous symbols: [ "SCN2A1", "SCN2A2" ]

Links

ENSG00000136531 ∙ NCBI:6326 ∙ OMIM:182390 ∙ HGNC:10588 ∙ Uniprot:Q99250 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 11 (Definitive), mode of inheritance: AD
• seizures, benign familial infantile, 3 (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy (Supportive), mode of inheritance: AD
• West syndrome (Supportive), mode of inheritance: AD
• benign familial infantile epilepsy (Supportive), mode of inheritance: AD
• Dravet syndrome (Supportive), mode of inheritance: AD
• benign familial neonatal-infantile seizures (Supportive), mode of inheritance: AD
• malignant migrating partial seizures of infancy (Supportive), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
• episodic ataxia, type 9 (Strong), mode of inheritance: AD
• seizures, benign familial infantile, 3 (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy, 11 (Strong), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 11; Seizures, benign familial infantile, 3; Episodic ataxia, type 9	AD	Neurologic	In Epileptic encephalopathy, early infantile, 11 and Seizures, benign familial infantile, 3, individuals may manifest with seizures (among other findings), and specific knowledge of the underlying cause can help direct selection of optimal therapies for management based on the genetic etiology; In Episodic ataxia, type 9, individuals manifest with ataxic episodes, and treatment with acetazolamide has been reported to be effective in some patients	Neurologic	6660252; 3508699; 8734025; 11326335; 15048894; 15028761; 19786696; 20956790; 22029951; 22591750; 22612257; 23020937; 26645390; 28331464; 30415926; 30643928; 30870728; 30928199; 31487502

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SCN2A gene.

• Seizures, benign familial infantile, 3;Developmental and epileptic encephalopathy, 11 (80 variants)
• not provided (80 variants)
• Developmental and epileptic encephalopathy, 11;Seizures, benign familial infantile, 3 (47 variants)
• Complex neurodevelopmental disorder (43 variants)
• Developmental and epileptic encephalopathy, 11 (40 variants)
• Inborn genetic diseases (19 variants)
• Seizures, benign familial infantile, 3 (16 variants)
• Early infantile epileptic encephalopathy with suppression bursts (6 variants)
• Episodic ataxia, type 9 (6 variants)
• SCN2A-related disorder (4 variants)
• Intellectual disability (4 variants)
• See cases (2 variants)
• West syndrome (2 variants)
• Malignant migrating partial seizures of infancy (1 variants)
• Developmental disorder (1 variants)
• Early infantile epileptic encephalopathy with suppression bursts;West syndrome (1 variants)
• Seizures, benign familial infantile, 3;Developmental and epileptic encephalopathy, 11;Episodic ataxia, type 9 (1 variants)
• Seizure (1 variants)
• West syndrome;Early infantile epileptic encephalopathy with suppression bursts (1 variants)
• Seizures, benign familial infantile, 3;SCN2A-related generalized epilepsy with febrile seizures plus (1 variants)
• Epileptic encephalopathy (1 variants)
• unclassified developmental and epileptic encephalopathy (1 variants)
• Autism spectrum disorder (1 variants)
• Benign familial infantile epilepsy (1 variants)
• Infantile spasms (1 variants)
• Benign familial neonatal-infantile seizures 1;Seizures, benign familial infantile, 3;SCN2A-related generalized epilepsy with febrile seizures plus;Developmental and epileptic encephalopathy, 11 (1 variants)
• Seizures, benign familial infantile, 3;Episodic ataxia, type 9;Developmental and epileptic encephalopathy, 11 (1 variants)
• Benign Neonatal Epilepsy (1 variants)
• Epileptic encephalopathy, infantile or early childhood (1 variants)
• Non-syndromic intellectual disability (1 variants)
• Epilepsy of infancy with migrating focal seizures (1 variants)
• benign sporadic infantile epilepsy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SCN2A 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			17	423	10	450
missense	86	220	869	26	3	1204
nonsense	48	18	3			69
start loss		1				1
frameshift	80	18	1			99
inframe indel	1	5	15			21
splice donor/acceptor (+/-2bp)	19	11	1			31
splice region		5	35	51	4	95
non coding		1	53	161	109	324
Total	234	274	959	610	122

Highest pathogenic variant AF is 0.00000658

Variants in SCN2A

This is a list of pathogenic ClinVar variants found in the SCN2A region.

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

Position	Type	Phenotype	Significance	ClinVar
2-165293790-G-C			Benign (May 20, 2019)
2-165293848-G-A		Seizures, benign familial infantile, 3	Uncertain significance (Jan 13, 2018)
2-165293859-C-T		Seizures, benign familial infantile, 3	Uncertain significance (Jan 12, 2018)
2-165294010-TA-T		Seizures, benign familial infantile, 3 • Early Infantile Epileptic Encephalopathy, Autosomal Dominant	Conflicting classifications of pathogenicity (Sep 24, 2019)
2-165294010-TAA-T		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Conflicting classifications of pathogenicity (Jan 20, 2021)
2-165294010-TAAA-T			Likely benign (Feb 24, 2022)
2-165294011-A-T		Seizures, benign familial infantile, 3	Uncertain significance (Jan 13, 2018)
2-165294010-T-TAA		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Conflicting classifications of pathogenicity (Feb 21, 2020)
2-165294010-T-TAAA		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Uncertain significance (Jun 14, 2016)
2-165294015-A-C		Seizures, benign familial infantile, 3	Uncertain significance (Apr 27, 2017)
2-165294036-AAAG-A		Seizures, benign familial infantile, 3 • Early Infantile Epileptic Encephalopathy, Autosomal Dominant	Uncertain significance (Jun 14, 2016)
2-165294037-AAG-A		Seizures, benign familial infantile, 3 • Early Infantile Epileptic Encephalopathy, Autosomal Dominant	Uncertain significance (Jun 14, 2016)
2-165294038-AG-A		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Uncertain significance (Jun 14, 2016)
2-165294039-G-A		Seizures, benign familial infantile, 3	Uncertain significance (Jan 12, 2018)
2-165294040-A-T		Seizures, benign familial infantile, 3	Uncertain significance (Apr 27, 2017)
2-165294039-G-GAA		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Uncertain significance (Jun 14, 2016)
2-165294039-G-GAT		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Uncertain significance (Jun 14, 2016)
2-165294040-A-AT		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Uncertain significance (Jun 14, 2016)
2-165294040-A-ATT		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Uncertain significance (Jun 14, 2016)
2-165294040-A-AAAT		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Uncertain significance (Jun 14, 2016)
2-165294040-A-AGAT		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Uncertain significance (Jun 14, 2016)
2-165294040-A-ATTT			Benign (Sep 01, 2022)
2-165294040-A-AAAAT		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Uncertain significance (Jun 14, 2016)
2-165294040-A-AAATT		Seizures, benign familial infantile, 3 • Early Infantile Epileptic Encephalopathy, Autosomal Dominant	Uncertain significance (Jun 14, 2016)
2-165294040-A-AGATT		Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3	Uncertain significance (Jun 14, 2016)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SCN2A	protein_coding	protein_coding	ENST00000357398	26	152907

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	2.55e-10	125727	0	4	125731	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.46	469	1.06e+3	0.442	0.0000572	13382
Missense in Polyphen		126	481.11	0.2619		6144
Synonymous	-0.127	374	371	1.01	0.0000205	3708
Loss of Function	7.92	5	82.7	0.0605	0.00000468	1036

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.00000882	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000329	0.000326

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. {ECO:0000269|PubMed:1325650, ECO:0000269|PubMed:17021166, ECO:0000269|PubMed:28256214}.
• Disease: DISEASE: Seizures, benign familial infantile, 3 (BFIS3) [MIM:607745]: A form of benign familial infantile epilepsy, a neurologic disorder characterized by afebrile seizures occurring in clusters during the first year of life, without neurologic sequelae. BFIS3 inheritance is autosomal dominant. {ECO:0000269|PubMed:11371648, ECO:0000269|PubMed:12243921, ECO:0000269|PubMed:15048894, ECO:0000269|PubMed:16417554, ECO:0000269|PubMed:17021166, ECO:0000269|PubMed:17386050, ECO:0000269|PubMed:18479388, ECO:0000269|PubMed:20371507, ECO:0000269|PubMed:22612257, ECO:0000269|PubMed:23360469, ECO:0000269|PubMed:23758435, ECO:0000269|PubMed:25982755, ECO:0000269|PubMed:26291284}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 11 (EIEE11) [MIM:613721]: An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. {ECO:0000269|PubMed:19783390, ECO:0000269|PubMed:19786696, ECO:0000269|PubMed:20956790, ECO:0000269|PubMed:22677033, ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23195492, ECO:0000269|PubMed:23550958, ECO:0000269|PubMed:23662938, ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:23935176, ECO:0000269|PubMed:23988467, ECO:0000269|PubMed:24463883, ECO:0000269|PubMed:24579881, ECO:0000269|PubMed:24659627, ECO:0000269|PubMed:24710820, ECO:0000269|PubMed:25457084, ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:26138355, ECO:0000269|PubMed:26291284, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in SCN2A are associated with autism spectrum disorders (ASD). It seems that mutations resulting in sodium channel gain of function and increased neuron excitability lead to infantile seizures, whereas variants resulting in sodium channel loss of function and decrease neruon excitability are associated with ASD. {ECO:0000269|PubMed:28256214}.
• 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: 0.344

Intolerance Scores

• loftool: 0.00145
• rvis_EVS: -1.99
• rvis_percentile_EVS: 1.77

Haploinsufficiency Scores

• pHI: 0.646
• hipred: Y
• hipred_score: 0.778
• ghis: 0.624

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.710

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Scn2a
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism 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); hematopoietic system phenotype; 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); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: sodium ion transport;intrinsic apoptotic signaling pathway in response to osmotic stress;neuronal action potential;regulation of ion transmembrane transport;sodium ion transmembrane transport;myelination;neuron apoptotic process;membrane depolarization during action potential
• Cellular component: voltage-gated sodium channel complex;plasma membrane;integral component of plasma membrane;intercalated disc;T-tubule;axon;intrinsic component of plasma membrane;node of Ranvier;paranode region of axon;sodium channel complex;glutamatergic synapse;integral component of presynaptic membrane
• Molecular function: voltage-gated ion channel activity;voltage-gated sodium channel activity