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GeneBe

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

ENSG00000136531NCBI:6326OMIM:182390HGNC:10588Uniprot:Q99250AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

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
  • 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

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Developmental and epileptic encephalopathy 11; Seizures, benign familial infantile, 3; Episodic ataxia, type 9ADNeurologicIn 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 patientsNeurologic6660252; 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.

  • not provided (888 variants)
  • Seizures, benign familial infantile, 3;Developmental and epileptic encephalopathy, 11 (666 variants)
  • Developmental and epileptic encephalopathy, 11;Seizures, benign familial infantile, 3 (526 variants)
  • Seizures, benign familial infantile, 3 (206 variants)
  • Inborn genetic diseases (204 variants)
  • Developmental and epileptic encephalopathy, 11 (180 variants)
  • not specified (170 variants)
  • Complex neurodevelopmental disorder (96 variants)
  • Early Infantile Epileptic Encephalopathy, Autosomal Dominant (21 variants)
  • SCN2A-related condition (18 variants)
  • Episodic ataxia, type 9 (14 variants)
  • Early infantile epileptic encephalopathy with suppression bursts (13 variants)
  • Intellectual disability (11 variants)
  • See cases (10 variants)
  • Seizure (10 variants)
  • Seizures, benign familial infantile, 3;Developmental and epileptic encephalopathy, 11;Episodic ataxia, type 9 (9 variants)
  • Epileptic encephalopathy (8 variants)
  • Developmental and epileptic encephalopathy, 11;Seizures, benign familial infantile, 3;Episodic ataxia, type 9 (8 variants)
  • West syndrome (6 variants)
  • SCN2A-related disorder (5 variants)
  • Developmental disorder (4 variants)
  • SCN2A-Related Disorders (4 variants)
  • Episodic ataxia, type 9;Developmental and epileptic encephalopathy, 11;Seizures, benign familial infantile, 3 (3 variants)
  • Benign familial infantile epilepsy (3 variants)
  • Infantile spasms (3 variants)
  • Epilepsy of infancy with migrating focal seizures (3 variants)
  • Early infantile epileptic encephalopathy with suppression bursts;West syndrome (2 variants)
  • Developmental and epileptic encephalopathy, 11;Episodic ataxia, type 9;Seizures, benign familial infantile, 3 (2 variants)
  • unclassified developmental and epileptic encephalopathy (2 variants)
  • Malignant migrating partial seizures of infancy (2 variants)
  • Neurodevelopmental disorder (2 variants)
  • Neurodevelopmental delay (2 variants)
  • 9 conditions (2 variants)
  • Autism spectrum disorder (2 variants)
  • Febrile seizure (within the age range of 3 months to 6 years) (2 variants)
  • Hemiplegia/hemiparesis (1 variants)
  • Severe myoclonic epilepsy in infancy (1 variants)
  • Episodic ataxia, type 9;Seizures, benign familial infantile, 3;Developmental and epileptic encephalopathy, 11 (1 variants)
  • Lennox-Gastaut syndrome (1 variants)
  • Developmental and epileptic encephalopathy, 30 (1 variants)
  • SCN2A-related generalized epilepsy with febrile seizures plus (1 variants)
  • SCN2A-related generalized epilepsy with febrile seizures plus;Benign familial neonatal-infantile seizures 1;Seizures, benign familial infantile, 3;Developmental and epileptic encephalopathy, 11 (1 variants)
  • SCN2A-mediated disorder (1 variants)
  • Benign familial neonatal-infantile seizures 1;Developmental and epileptic encephalopathy, 11;Intellectual disability (1 variants)
  • Dystonia 12 (1 variants)
  • Seizures, benign familial infantile, 3;Episodic ataxia, type 9;Developmental and epileptic encephalopathy, 11 (1 variants)
  • Epileptic encephalopathy, infantile or early childhood (1 variants)
  • benign sporadic infantile epilepsy (1 variants)
  • Pyridoxine-dependent epilepsy (1 variants)
  • Global developmental delay (1 variants)
  • Spastic ataxia (1 variants)
  • Autism Spectrum Disorder with Intellectual Disability (1 variants)
  • Marfanoid habitus and intellectual disability (1 variants)
  • Childhood epilepsy with centrotemporal spikes (1 variants)
  • SCN2A-related generalized epilepsy with febrile seizures plus;Seizures, benign familial infantile, 3 (1 variants)
  • History of neurodevelopmental disorder (1 variants)
  • West syndrome;Early infantile epileptic encephalopathy with suppression bursts (1 variants)
  • Focal epilepsy (1 variants)
  • Vertigo;Hereditary episodic ataxia;Seizure (1 variants)
  • Autism;Developmental and epileptic encephalopathy, 76;Seizures, benign familial infantile, 3;Episodic ataxia, type 9 (1 variants)
  • Benign Neonatal Epilepsy (1 variants)
  • Non-syndromic intellectual disability (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
18
clinvar
342
clinvar
12
clinvar
372
missense
65
clinvar
208
clinvar
763
clinvar
20
clinvar
2
clinvar
1058
nonsense
42
clinvar
17
clinvar
3
clinvar
62
start loss
1
clinvar
1
frameshift
67
clinvar
18
clinvar
1
clinvar
86
inframe indel
1
clinvar
4
clinvar
14
clinvar
19
splice donor/acceptor (+/-2bp)
17
clinvar
10
clinvar
1
clinvar
28
splice region
5
28
43
4
80
non coding
1
clinvar
53
clinvar
124
clinvar
109
clinvar
287
Total 192 259 853 486 123

Highest pathogenic variant AF is 0.0000131

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)1245138
2-165293848-G-A Seizures, benign familial infantile, 3 Uncertain significance (Jan 13, 2018)331704
2-165293859-C-T Seizures, benign familial infantile, 3 Uncertain significance (Jan 12, 2018)331705
2-165294010-TA-T Seizures, benign familial infantile, 3 • Early Infantile Epileptic Encephalopathy, Autosomal Dominant Conflicting classifications of pathogenicity (Sep 24, 2019)331708
2-165294010-TAA-T Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Conflicting classifications of pathogenicity (Jan 20, 2021)331709
2-165294010-TAAA-T Likely benign (Feb 24, 2022)1703351
2-165294011-A-T Seizures, benign familial infantile, 3 Uncertain significance (Jan 13, 2018)894299
2-165294010-T-TAA Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Conflicting classifications of pathogenicity (Feb 21, 2020)331706
2-165294010-T-TAAA Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Uncertain significance (Jun 14, 2016)331707
2-165294015-A-C Seizures, benign familial infantile, 3 Uncertain significance (Apr 27, 2017)894300
2-165294036-AAAG-A Seizures, benign familial infantile, 3 • Early Infantile Epileptic Encephalopathy, Autosomal Dominant Uncertain significance (Jun 14, 2016)331710
2-165294037-AAG-A Seizures, benign familial infantile, 3 • Early Infantile Epileptic Encephalopathy, Autosomal Dominant Uncertain significance (Jun 14, 2016)331711
2-165294038-AG-A Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Uncertain significance (Jun 14, 2016)331712
2-165294039-G-A Seizures, benign familial infantile, 3 Uncertain significance (Jan 12, 2018)331713
2-165294040-A-T Seizures, benign familial infantile, 3 Uncertain significance (Apr 27, 2017)892840
2-165294039-G-GAA Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Uncertain significance (Jun 14, 2016)331715
2-165294039-G-GAT Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Uncertain significance (Jun 14, 2016)331714
2-165294040-A-AT Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Uncertain significance (Jun 14, 2016)331723
2-165294040-A-ATT Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Uncertain significance (Jun 14, 2016)331724
2-165294040-A-AAAT Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Uncertain significance (Jun 14, 2016)331717
2-165294040-A-AGAT Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Uncertain significance (Jun 14, 2016)331721
2-165294040-A-ATTT Benign (Sep 01, 2022)2651482
2-165294040-A-AAAAT Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Uncertain significance (Jun 14, 2016)331716
2-165294040-A-AAATT Seizures, benign familial infantile, 3 • Early Infantile Epileptic Encephalopathy, Autosomal Dominant Uncertain significance (Jun 14, 2016)331718
2-165294040-A-AGATT Early Infantile Epileptic Encephalopathy, Autosomal Dominant • Seizures, benign familial infantile, 3 Uncertain significance (Jun 14, 2016)331722

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
SCN2Aprotein_codingprotein_codingENST00000357398 26152907
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
1.002.55e-10125727041257310.0000159
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense6.464691.06e+30.4420.000057213382
Missense in Polyphen126481.110.26196144
Synonymous-0.1273743711.010.00002053708
Loss of Function7.92582.70.06050.000004681036

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.000.00
Ashkenazi Jewish0.000.00
East Asian0.000.00
Finnish0.00004620.0000462
European (Non-Finnish)0.000008820.00000879
Middle Eastern0.000.00
South Asian0.000.00
Other0.0003290.000326

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

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

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