chr3-14152376-T-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004628.5(XPC):c.2074A>T(p.Lys692*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,260 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004628.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152156Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461104Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726742
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74328
ClinVar
Submissions by phenotype
Xeroderma pigmentosum, group C Pathogenic:2
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Xeroderma pigmentosum Pathogenic:1
Variant summary: The XPC c.2074A>T (p.Lys692*) variant results in a premature termination codon, predicted to cause a truncated or absent XPC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. These predictions were confirmed by Khan et al (2006) who showed severely reduced level of mRNA and lack of protein expression in in vitro assay. This variant was found in 1/108904 control chromosomes at a frequency of 0.0000092, which does not exceed the estimated maximal expected allele frequency of a pathogenic XPC variant (0.0014142). This variant has been reported in at least two unrelated patients with Xeroderma Pigmentosum (Khan_2006, Kuschal_2013). In addition, truncation variants downstream of this position, such as c.2152C>T (p.R718*), c.2262delC (p.Asn754Lysfs) and c.2251-1G>C have been classified as "Pathogenic" by reputable databases/diagnostic laboratories . Taken together, this variant is classified as Pathogenic. -
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Lys692*) in the XPC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XPC are known to be pathogenic (PMID: 23173980, 25256075). This variant is present in population databases (rs374117852, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 16081512). ClinVar contains an entry for this variant (Variation ID: 496267). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at