chr5-60944972-C-A
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000082.4(ERCC8):c.37G>T(p.Glu13*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000082.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- Leigh syndromeInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P
- mitochondrial complex I deficiency, nuclear type 10Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- Leigh syndrome with leukodystrophyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- mitochondrial complex I deficiencyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ERCC8 | NM_000082.4 | c.37G>T | p.Glu13* | stop_gained | Exon 1 of 12 | ENST00000676185.1 | NP_000073.1 | |
NDUFAF2 | NM_174889.5 | c.-284C>A | upstream_gene_variant | ENST00000296597.10 | NP_777549.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152150Hom.: 0 Cov.: 30 show subpopulations
GnomAD2 exomes AF: 0.0000755 AC: 19AN: 251494 AF XY: 0.0000809 show subpopulations
GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461866Hom.: 0 Cov.: 30 AF XY: 0.0000550 AC XY: 40AN XY: 727236 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152150Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3AN XY: 74342 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Nonsense 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: 25333069, 29572252, 29742419, 14661080, 15744458, 19894250) -
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This sequence change creates a premature translational stop signal (p.Glu13*) in the ERCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC8 are known to be pathogenic (PMID: 29572252). This variant is present in population databases (rs121434324, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with Cockayne syndrome (PMID: 14661080, 29572252). ClinVar contains an entry for this variant (Variation ID: 1716). For these reasons, this variant has been classified as Pathogenic. -
Cockayne syndrome type 1 Pathogenic:3
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NM_000082.3(ERCC8):c.37G>T(E13*) is classified as pathogenic in the context of ERCC8-related disorders. Sources cited for classification include the following: PMID 19894250 and 14661080. Classification of NM_000082.3(ERCC8):c.37G>T(E13*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
The p.Glu13X variant in ERCC8 has been reported in 2 compound heterozygous and 3 homozgyous individuals with Cockayne syndrome (Cao 2004 PMID:14661080, Laugel 2010 PMID: 19894250, Calmels 2018 PMID: 29572252). It has been identified in 0.139% (14/10080) of Ashkenazi Jewish chromosomes and 0.004% of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It is also reported in ClinVar (Variation ID: 1716). This nonsense variant leads to a premature termination codon at position 13, which is predicted to lead to a truncated or absent protein. Loss of function of the ERCC8 gene is an established disease mechanism in autosomal recessive Cockayne syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cockayne syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong. -
Cockayne syndrome type 1;C3553298:UV-sensitive syndrome 2 Pathogenic:1
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Cockayne syndrome Pathogenic:1
Variant summary: ERCC8 c.37G>T (p.Glu13X) 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. The variant allele was found at a frequency of 7.6e-05 in 251494 control chromosomes (gnomAD). c.37G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Cockayne Syndrome (Cao_2004, Ridley_2005, Nardo_2009, Calmels_2018). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of protein product and greatly decreased cell survival after UV irradiation in patient derived fibroblasts (Ridley_2005, Nardo_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. 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