rs786205168
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000124.4(ERCC6):βc.1518delβ(p.Lys506AsnfsTer37) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000027 ( 0 hom. )
Consequence
ERCC6
NM_000124.4 frameshift
NM_000124.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.12
Genes affected
ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 10-49505891-GC-G is Pathogenic according to our data. Variant chr10-49505891-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC6 | NM_000124.4 | c.1518del | p.Lys506AsnfsTer37 | frameshift_variant | 6/21 | ENST00000355832.10 | |
ERCC6 | NM_001346440.2 | c.1518del | p.Lys506AsnfsTer37 | frameshift_variant | 6/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC6 | ENST00000355832.10 | c.1518del | p.Lys506AsnfsTer37 | frameshift_variant | 6/21 | 1 | NM_000124.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460848Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 726714
GnomAD4 exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cockayne syndrome type 2 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Claritas Genomics | Aug 26, 2013 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic mutation in a 8-month-old female with global delays, microcephaly, congenital cataracts, failure to thrive, hypotonia, micrognathia - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2023 | This sequence change creates a premature translational stop signal (p.Lys506Asnfs*37) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Cockayne syndrome (PMID: 9443879, 29572252). ClinVar contains an entry for this variant (Variation ID: 190150). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at