rs786205053
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000097.7(CPOX):c.127_131dupGCAGC(p.Gly45GlnfsTer93) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000052 in 1,345,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000097.7 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CPOX | ENST00000647941.2 | c.127_131dupGCAGC | p.Gly45GlnfsTer93 | frameshift_variant | Exon 1 of 7 | NM_000097.7 | ENSP00000497326.1 | |||
CPOX | ENST00000513674.1 | n.127_131dupGCAGC | non_coding_transcript_exon_variant | Exon 1 of 4 | 5 | ENSP00000424924.1 | ||||
CPOX | ENST00000515041.1 | n.233_237dupGCAGC | non_coding_transcript_exon_variant | Exon 1 of 3 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151930Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000419 AC: 5AN: 1193606Hom.: 0 Cov.: 31 AF XY: 0.00000690 AC XY: 4AN XY: 579570
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151930Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74216
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Gly45Glnfs*93) in the CPOX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPOX are known to be pathogenic (PMID: 9888388). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal dominant CPOX-related conditions (PMID: 8990017, 30476629). ClinVar contains an entry for this variant (Variation ID: 454). For these reasons, this variant has been classified as Pathogenic. -
The c.127_131dupGCAGC variant in the CPOX gene has been reported previously using alternate nomenclature 129ins5 in a patient with coproporphyria (Lamoril et al., 1997). The c.127_131dupGCAGC variant causes a frameshift starting with codon Glycine 45, changes this amino acid to a Glutamine residue, and creates a premature Stop codon at position 93 of the new reading frame, denoted p.Gly45GlnfsX93. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.127_131dupGCAGC variant was not observed in approximately 767 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.127_131dupGCAGC as a pathogenic variant. -
Coproporphyria Pathogenic:1
- -
CPOX-related disorder Pathogenic:1
The CPOX c.127_131dup5 variant is predicted to result in a frameshift and premature protein termination (p.Gly45Glnfs*93). This variant was reported in the heterozygous state in individuals with coproporphyria (described as 129ins5, Lamoril et al. 1997. PubMed ID: 8990017; Borrero Corte et al. 2019. PubMed ID: 30476629). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in CPOX 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