rs750622098
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_000082.4(ERCC8):c.1095dupA(p.Tyr366fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
ERCC8
NM_000082.4 frameshift
NM_000082.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.459
Genes affected
ERCC8 (HGNC:3439): (ERCC excision repair 8, CSA ubiquitin ligase complex subunit) This gene encodes a WD repeat protein, which interacts with Cockayne syndrome type B (CSB) protein and with p44 protein, a subunit of the RNA polymerase II transcription factor IIH. Mutations in this gene have been identified in patients with hereditary disease Cockayne syndrome (CS). CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0806 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ERCC8 | NM_000082.4 | c.1095dupA | p.Tyr366fs | frameshift_variant | 11/12 | ENST00000676185.1 | NP_000073.1 | |
ERCC8 | NM_001007233.3 | c.921dupA | p.Tyr308fs | frameshift_variant | 12/13 | NP_001007234.1 | ||
ERCC8 | NM_001290285.2 | c.636dupA | p.Tyr213fs | frameshift_variant | 10/11 | NP_001277214.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ERCC8 | ENST00000676185.1 | c.1095dupA | p.Tyr366fs | frameshift_variant | 11/12 | NM_000082.4 | ENSP00000501614.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251446Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135894
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461442Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727074
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74394
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cockayne syndrome type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 21, 2017 | - - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at