rs764868582
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000400.4(ERCC2):c.2080C>T(p.Pro694Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P694P) has been classified as Likely benign.
Frequency
Consequence
NM_000400.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC2 | NM_000400.4 | c.2080C>T | p.Pro694Ser | missense_variant | 22/23 | ENST00000391945.10 | |
ERCC2 | XM_011526611.3 | c.2002C>T | p.Pro668Ser | missense_variant | 21/22 | ||
ERCC2 | XR_001753633.3 | n.2113C>T | non_coding_transcript_exon_variant | 22/24 | |||
ERCC2 | XR_007066680.1 | n.2035C>T | non_coding_transcript_exon_variant | 21/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC2 | ENST00000391945.10 | c.2080C>T | p.Pro694Ser | missense_variant | 22/23 | 1 | NM_000400.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251302Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135852
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461790Hom.: 0 Cov.: 37 AF XY: 0.00000688 AC XY: 5AN XY: 727196
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 02, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 694 of the ERCC2 protein (p.Pro694Ser). This variant is present in population databases (rs764868582, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ERCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 523368). 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2023 | The p.P694S variant (also known as c.2080C>T), located in coding exon 22 of the ERCC2 gene, results from a C to T substitution at nucleotide position 2080. The proline at codon 694 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Leukodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at