rs769825203
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001040142.2(SCN2A):c.1385C>A(p.Ala462Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A462V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001040142.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.1385C>A | p.Ala462Glu | missense_variant, splice_region_variant | 11/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.1385C>A | p.Ala462Glu | missense_variant, splice_region_variant | 11/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.1385C>A | p.Ala462Glu | missense_variant, splice_region_variant | 11/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.1385C>A | p.Ala462Glu | missense_variant, splice_region_variant | 11/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248128Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134542
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461464Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727032
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 13, 2023 | This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 462 of the SCN2A protein (p.Ala462Glu). - |
SCN2A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 19, 2022 | The SCN2A c.1385C>A variant is predicted to result in the amino acid substitution p.Ala462Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-166171982-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at