rs121434326
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000082.4(ERCC8):āc.613G>Cā(p.Ala205Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,458,226 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 (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.000011 ( 0 hom. )
Consequence
ERCC8
NM_000082.4 missense
NM_000082.4 missense
Scores
6
12
1
Clinical Significance
Conservation
PhyloP100: 5.12
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 Pathogenic. Variant got 14 ACMG points.
PM1
In a strand (size 5) in uniprot entity ERCC8_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000082.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.895
PP5
Variant 5-60902446-C-G is Pathogenic according to our data. Variant chr5-60902446-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-60902446-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC8 | NM_000082.4 | c.613G>C | p.Ala205Pro | missense_variant | 7/12 | ENST00000676185.1 | |
ERCC8 | NM_001007233.3 | c.439G>C | p.Ala147Pro | missense_variant | 8/13 | ||
ERCC8 | NM_001290285.2 | c.154G>C | p.Ala52Pro | missense_variant | 6/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC8 | ENST00000676185.1 | c.613G>C | p.Ala205Pro | missense_variant | 7/12 | NM_000082.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000638 AC: 16AN: 250866Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135582
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1458226Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9AN XY: 725542
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 205 of the ERCC8 protein (p.Ala205Pro). This variant is present in population databases (rs121434326, gnomAD 0.05%). This missense change has been observed in individual(s) with Cockayne syndrome (PMID: 14661080, 32048102). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1718). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERCC8 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ERCC8 function (PMID: 16949367, 29531219). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2023 | Published functional studies demonstrate a damaging effect (Pines et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17084038, 14661080, 23571135, 28333167, 16865293, 29531219, 25653723, 19894250, 32048102) - |
Cockayne syndrome type 1 Pathogenic:1Uncertain:1
Uncertain significance, flagged submission | clinical testing | Counsyl | May 12, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2004 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at A205 (P = 0.0221);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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