Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_SupportingPP3_Moderate
The NM_000400.4(ERCC2):c.934G>T(p.Asp312Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. 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. D312N) has been classified as Likely benign.
Verdict is Uncertain_significance. Variant got 3 ACMG points.
GnomAD3 genomesCov.: 33 GnomAD3 exomes AF: 0.00000707AC: 1AN: 141480Hom.: 0 AF XY: 0.0000130AC XY: 1AN XY: 77124 GnomAD4 exome AF: 0.00000144AC: 2AN: 1391598Hom.: 0 AF XY: 0.00000291AC XY: 2AN XY: 686696
Submissions by phenotype
|Uncertain significance, criteria provided, single submitter||clinical testing||Invitae||Jan 15, 2022||This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 312 of the ERCC2 protein (p.Asp312Tyr). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ERCC2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -|
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