rs121917903
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000124.4(ERCC6):c.229C>T(p.Arg77Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,084 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R77R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000124.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC6 | NM_000124.4 | c.229C>T | p.Arg77Ter | stop_gained | 2/21 | ENST00000355832.10 | |
ERCC6 | NM_001277058.2 | c.229C>T | p.Arg77Ter | stop_gained | 2/6 | ENST00000447839.7 | |
ERCC6 | NM_001346440.2 | c.229C>T | p.Arg77Ter | stop_gained | 2/21 | ||
ERCC6 | NM_001277059.2 | c.229C>T | p.Arg77Ter | stop_gained | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC6 | ENST00000355832.10 | c.229C>T | p.Arg77Ter | stop_gained | 2/21 | 1 | NM_000124.4 | P1 | |
ERCC6 | ENST00000447839.7 | c.229C>T | p.Arg77Ter | stop_gained | 2/6 | 2 | NM_001277058.2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251438Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135906
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727248
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74358
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 16, 2023 | This sequence change creates a premature translational stop signal (p.Arg77*) in the ERCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 18628313, 29572252). This variant is present in population databases (rs121917903, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of Cockayne syndrome (PMID: 15486090, 30111349). ClinVar contains an entry for this variant (Variation ID: 1708). For these reasons, this variant has been classified as Pathogenic. - |
Cockayne syndrome type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 29, 2015 | - - |
Cockayne syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2023 | Variant summary: ERCC6 c.229C>T (p.Arg77X) results in a premature termination codon and is confirmed to cause absence of the protein (Horibata_2011), which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251438 control chromosomes (gnomAD). c.229C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with UV-sensitive syndrome (Horibata_2004, Horibata_2011), and Cockayne syndrome (Tonduti_2018, Sun_2019). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
UV-sensitive syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at