rs754673606
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004628.5(XPC):c.2251-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_004628.5 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
XPC | NM_004628.5 | c.2251-1G>C | splice_acceptor_variant, intron_variant | ENST00000285021.12 | NP_004619.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
XPC | ENST00000285021.12 | c.2251-1G>C | splice_acceptor_variant, intron_variant | 1 | NM_004628.5 | ENSP00000285021.8 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249174Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135180
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461668Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 727104
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74372
ClinVar
Submissions by phenotype
Xeroderma pigmentosum, group C Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Claritas Genomics | Oct 17, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 31, 2022 | ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated, PM3 strong, PP1 supporting - |
Pathogenic, criteria provided, single submitter | research | Medical Molecular Genetics Department, National Research Center | Dec 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Dr.Nikuei Genetic Center | - | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | DNA Repair Laboratory, Institute of Biomedical Sciences - University of Sao Paulo | Mar 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 19, 2021 | NM_004628.4(XPC):c.2251-1G>C is a canonical splice variant classified as pathogenic in the context of xeroderma pigmentosum group C. c.2251-1G>C has been observed in cases with relevant disease (PMID: 21482201). Functional assessments of this variant are not available in the literature. c.2251-1G>C has been observed in population frequency databases (gnomAD: AFR 0.04%). In summary, NM_004628.4(XPC):c.2251-1G>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | This sequence change affects an acceptor splice site in intron 12 of the XPC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs754673606, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with xeroderma pigmentosum (PMID: 21482201). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190213). Studies have shown that disruption of this splice site results in abnormal splicing, including skipping of exon 13, retention of intron 12, and/or a deletion of 44 nucleotides in exon 13 and introduces a premature termination codon (PMID: 21482201). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 25, 2022 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31930276, 21482201, 29753700, 26884178, 29569758, 31589614, 33672602) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2021 | - - |
Xeroderma pigmentosum Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 11, 2017 | Variant summary: The XPC c.2251-1G>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing. Functional studies proved the exon skipping and the absence of the XPC protein associated with impaired DNA synthesis in XP patients cultured fibroblasts (Cartault_DNA_Repair_2011, Fassihi_PNAS_2016). This variant was found in 2/120678 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic XPC variant (0.0014142). This variant is reported in multiple homozygous XP patients (Cartault_DNA_Repair_2011, Fassihi_PNAS_2016). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
XPC-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 21, 2023 | The XPC c.2251-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in individuals with xeroderma pigmentosum (see for example, Santiago et al. 2020. PubMed ID: 32239545; Fassihi et al. 2016. PubMed ID: 26884178; reported as IVS 12-1G>C in Cartault et al. 2011. PubMed ID: 21482201). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice acceptor site in XPC are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at