SCN2A

Gene Facts

• HGNC Symbol: SCN2A (HGNC:10588)
• HGNC Name: sodium voltage-gated channel alpha subunit 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: SCN2A1, SCN2A2
• Alias symbols: Nav1.2, HBSCII, HBSCI
• %HI: 4.08
• pLI: 1
• LOEUF: 0.16
• Cytoband: 2q24.3
• Genomic Coordinates:

  GRCh37/hg19:	chr2:166095924-166248814
  GRCh38/hg38:	chr2:165239414-165392304

• MANE Select Transcript: NM_001040142.2 ENST00000375437.7
• MANE Plus Clinical Transcript(s):

  NM_001371246.1 ENST00000631182.3 (Read more about MANE Plus Clinical)

• 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:1325650, PubMed:17021166, PubMed:28256214, PubMed:29844171). Implicated in the regulation of hippocampal replay occurring within sharp wave ripples (SPW-R) important for memory (By simi... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-7043
• ClinGen Curation ID: CCID:007808
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 04/22/2020

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Complex Neurodevelopmental Disorder

HI Evidence

• PUBMED: 22495306
  Sanders et al. 2012 report WES data on probands from the Simons Simplex Collection (SSC) autism cohort. They found 279 de novo coding mutations, with 2 nonsense changes (G1013X and C959X) in SCN2A in the probands (not in the sibs). These individuals did not have a history of seizures.
• PUBMED: 15028761
  Kamiya et al. 2004 analyzed SCN2A in 20 patients diagnosed with intractable childhood epilepsies. They found a de novo nonsense change (R102X) resulting in a truncated protein in a patient with delayed onset of early infantile epileptic encephalopathy-11 (613721). The seizures began at 1 year 7 months, and the patient was autistic.
• PUBMED: 28379373, 29655203
  Wolff M, et al (2017) reported SCN2A variants in 34 patients with encephalopathy with late onset epilepsy (West syndrome, Lennox-Gastaut syndrome, myoclonicatonic epilepsy, and focal epilepsies with an ESES-like picture), intellectual disability and/or autism without epilepsy. There are 8 patients with de novo nonsense variants (all confirmed by Sanger sequencing). The rest are missense/splicing variants. Two selected de novo missense variants were confirmed to be loss-of-function variants by standard whole-cell patch clamp recording functional study. Lindy AS, et al (2018) reviewed the genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. They reported at least 4 truncating variants (nonsense or frame-shift, detected by NGS) of SCN2A. They reported that 90.2% of variants in SCN2A were de novo.

• HI Evidence Comments: In addition, missense changes in SCN2A have been associated with benign familial infantile seizures (607745). After reviewing genetic testing results of 71 unpublished patients and 130 published cases, Wolff M, et al (28379373) suggested that there are two distinct groups of SCN2A variants. One group contains missense variants with gain-of-function and associated with early infantile epilepsy with onset before 3 months of age. The other group frequently contains loss-of-function variants (truncations and splice site variants, and missense mutations with loss-of-function effects), and associated with later onset epilepsy, intellectual disability and/or autism without epilepsy.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Simonetti et al PMID: 23016767 review 2q24 duplications in patients with early onset epilepsy (3 patients in this study, along with patients from other studies). None of the reported duplications include only the SCN2A gene.