chr3-98580709-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_000097.7(CPOX):c.1339C>T(p.Arg447Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000313 in 1,614,170 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000097.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CPOX | NM_000097.7 | c.1339C>T | p.Arg447Cys | missense_variant | Exon 7 of 7 | ENST00000647941.2 | NP_000088.3 | |
CPOX | XM_005247125.5 | c.1173-2439C>T | intron_variant | Intron 5 of 5 | XP_005247182.1 | |||
CPOX | XR_001740025.3 | n.1280-2439C>T | intron_variant | Intron 5 of 6 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000250 AC: 38AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000395 AC: 99AN: 250462Hom.: 0 AF XY: 0.000435 AC XY: 59AN XY: 135522
GnomAD4 exome AF: 0.000320 AC: 468AN: 1461840Hom.: 3 Cov.: 33 AF XY: 0.000345 AC XY: 251AN XY: 727226
GnomAD4 genome AF: 0.000249 AC: 38AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74482
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Identified in the heterozygous and homozygous state in individuals with clinical features of CPOX-related porphyria referred for genetic testing at GeneDx and in the published literature (PMID: 33763395, 27959697, 11309681; elik et al. (2024) Gazi Medical Journal. 35 :76 https://openurl.ebsco.com/EPDB%3Agcd%3A8%3A29114392/detailv2?sid=ebsco%3Aplink%3Ascholar&id=ebsco%3Agcd%3A174987964&crl=c); Reported with a second CPOX variant on the same allele (in cis) in affected individuals from three families with hereditary coproporphyria, as well as without a second CPOX variant in an unaffected individual from one of these families (PMID: 12181641); Published functional studies demonstrate significantly reduced CPOX enzyme activity (PMID: 11309681); 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: 11309681, 27959697, 34426522, 31589614, 33763395, Wangetal2023[article], 12181641, Celik2024[article], 39267094) -
PP3, PS3 -
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 447 of the CPOX protein (p.Arg447Cys). This variant is present in population databases (rs28931603, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of coproporphyria (PMID: 11309681, 12181641, 27959697, 33763395). ClinVar contains an entry for this variant (Variation ID: 459). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CPOX protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CPOX function (PMID: 11309681). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary coproporphyria Uncertain:2
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Coproporphyria Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at