rs1233791234
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000400.4(ERCC2):βc.2005delβ(p.Arg669GlyfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. R669R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000400.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC2 | NM_000400.4 | c.2005del | p.Arg669GlyfsTer40 | frameshift_variant | 21/23 | ENST00000391945.10 | |
ERCC2 | XM_011526611.3 | c.1927del | p.Arg643GlyfsTer40 | frameshift_variant | 20/22 | ||
ERCC2 | XR_001753633.3 | n.2038del | non_coding_transcript_exon_variant | 21/24 | |||
ERCC2 | XR_007066680.1 | n.1960del | non_coding_transcript_exon_variant | 20/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC2 | ENST00000391945.10 | c.2005del | p.Arg669GlyfsTer40 | frameshift_variant | 21/23 | 1 | NM_000400.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251388Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461752Hom.: 0 Cov.: 37 AF XY: 0.0000316 AC XY: 23AN XY: 727178
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74480
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2023 | This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg669Glyfs*40) in the ERCC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC2 are known to be pathogenic (PMID: 9238033, 11335038, 19085937, 19934020). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 445466). This premature translational stop signal has been observed in individual(s) with clinical features of xeroderma pigmentosum and Cockayne syndrome (PMID: 7825573). - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 29, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 12, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in a patient with medulloblastoma (Waszek 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as c.2083delA; This variant is associated with the following publications: (PMID: 29753700, 7825573) - |
Xeroderma pigmentosum Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2024 | Variant summary: ERCC2 c.2005delA (p.Arg669GlyfsX40) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251388 control chromosomes. c.2005delA (also referred to as a deletion of adenine at base 2083) has been reported in the literature in at least one individual belonging to Xeroderma Pigmentosum Complementation Group D with clinical features of Xeroderma Pigmentosum and Cockayne Syndrome (e.g. Broughton_1995). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 7825573). ClinVar contains an entry for this variant (Variation ID: 445466). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Cerebrooculofacioskeletal syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 20, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at