rs765825423
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000124.4(ERCC6):βc.3952_3953delβ(p.Arg1318GlyfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. R1318R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000124.4 frameshift
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.3952_3953del | p.Arg1318GlyfsTer12 | frameshift_variant | 19/21 | ENST00000355832.10 | |
ERCC6 | NM_001346440.2 | c.3952_3953del | p.Arg1318GlyfsTer12 | frameshift_variant | 19/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC6 | ENST00000355832.10 | c.3952_3953del | p.Arg1318GlyfsTer12 | frameshift_variant | 19/21 | 1 | NM_000124.4 | P1 | |
ENST00000423283.1 | n.235-11321_235-11320del | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251212Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135778
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461428Hom.: 0 AF XY: 0.0000206 AC XY: 15AN XY: 727042
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Cerebrooculofacioskeletal syndrome 1;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0751038:Cockayne syndrome type 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 10, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The c.3952_3953delAG (p.R1318Gfs) variant is a frameshift deletion of two nucleotides predicted to result in a nonfunctional ERCC6 protein. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change creates a premature translational stop signal (p.Arg1318Glyfs*12) 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 (rs765825423, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome type B (PMID: 29572252). ClinVar contains an entry for this variant (Variation ID: 190171). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2023 | Reported in two unrelated patients with Cockayne syndrome who each harbored another variant in the ERCC6 gene in published literature (Calmels et al., 2018); Identified in a patient with a clinical diagnosis and family history of hearing loss, loss of ambulation, hypotonia, cerebellar ataxia and sensory neuropathy who underwent exome sequencing (Monies et al., 2019); this individual also harbored an intronic variant in ERCC6 though its clinical significance was considered to be unknown; 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; This variant is associated with the following publications: (PMID: 31130284, 29572252, 18628313, 9443879) - |
Cockayne syndrome type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Claritas Genomics | Oct 22, 2013 | - - |
Cockayne syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 23, 2022 | Variant summary: ERCC6 c.3952_3953delAG (p.Arg1318GlyfsX12) 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. Truncations downstream of this position have been classified as pathogenic in ClinVar database. The variant allele was found at a frequency of 2e-05 in 251212 control chromosomes (gnomAD). c.3952_3953delAG has been reported in the literature in two individuals affected with Cockayne Syndrome (Calmels_2018), one individual with clinical diagnosis and family history of hearing loss, loss of ambulation, hypotonia, cerebellar ataxia and sensory neuropathy (Monies_2019), one individual affected with acute lymphoblastic leukemia (Qin_2020) and one individual affected with malignant peritoneal mesothelioma (Hung_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at