rs140661535
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_001040142.2(SCN2A):c.1484C>A(p.Ser495Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S495C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001040142.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.1484C>A | p.Ser495Tyr | missense_variant | 11/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.1484C>A | p.Ser495Tyr | missense_variant | 11/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.1484C>A | p.Ser495Tyr | missense_variant | 11/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.1484C>A | p.Ser495Tyr | missense_variant | 11/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes AF: 0.00000660 AC: 1AN: 151426Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248470Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134514
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461770Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727168
GnomAD4 genome AF: 0.00000660 AC: 1AN: 151426Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 73904
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 | Jun 18, 2023 | This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 495 of the SCN2A protein (p.Ser495Tyr). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function. ClinVar contains an entry for this variant (Variation ID: 1378422). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. This variant is present in population databases (rs140661535, gnomAD 0.002%). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at