rs121913020
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000400.4(ERCC2):c.335G>A(p.Arg112His) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,406 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R112C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000400.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC2 | NM_000400.4 | c.335G>A | p.Arg112His | missense_variant | 5/23 | ENST00000391945.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC2 | ENST00000391945.10 | c.335G>A | p.Arg112His | missense_variant | 5/23 | 1 | NM_000400.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251144Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135762
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461188Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 726910
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74364
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 28, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25795128, 12820975, 25897079, 15494306, 18817897, 23232694, 23800062, 12458209, 25431422, 25605938, 10667598, 27982466, 27085493, 27262611, 7920640, 9758621, 25620205, 23221806, 30580289, 33670118) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 112 of the ERCC2 protein (p.Arg112His). This variant is present in population databases (rs121913020, gnomAD 0.008%). This missense change has been observed in individuals with trichothiodystrophy (PMID: 7920640, 9758621). This variant is also known as a G to A mutation at position 413. ClinVar contains an entry for this variant (Variation ID: 16784). 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 ERCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ERCC2 function (PMID: 25431422). For these reasons, this variant has been classified as Pathogenic. - |
Xeroderma pigmentosum, group D Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 15, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 28, 2022 | - - |
Cerebrooculofacioskeletal syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 16, 2024 | - - |
Trichothiodystrophy 1, photosensitive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 15, 2001 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at