rs786205053

chr3-98593373-G-GGCTGC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000097.7(CPOX):c.131_132insGCAGC(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:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: CPOX NM_000097.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.23

Genes affected

CPOX (HGNC:2321): (coproporphyrinogen oxidase) The protein encoded by this gene is the sixth enzyme of the heme biosynthetic pathway. The encoded enzyme is soluble and found in the intermembrane space of mitochondria. This enzyme catalyzes the stepwise oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen IX, a precursor of heme. Defects in this gene are a cause of hereditary coproporphyria (HCP).[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-98593373-G-GGCTGC is Pathogenic according to our data. Variant chr3-98593373-G-GGCTGC is described in ClinVar as [Pathogenic]. Clinvar id is 454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPOX	NM_000097.7	c.131_132insGCAGC	p.Gly45GlnfsTer93	frameshift_variant	1/7	ENST00000647941.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPOX	ENST00000647941.2	c.131_132insGCAGC	p.Gly45GlnfsTer93	frameshift_variant	1/7		NM_000097.7	P1
CPOX	ENST00000515041.1	n.237_238insGCAGC		non_coding_transcript_exon_variant	1/3	2
CPOX	ENST00000513674.1	c.131_132insGCAGC	p.Gly45GlnfsTer93	frameshift_variant, NMD_transcript_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151930 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000419 AC: 5 AN: 1193606 Hom.: 0 Cov.: 31 AF XY: 0.00000690 AC XY: 4 AN XY: 579570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000451

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000302

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74216

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	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. -

Coproporphyria Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1997

- -

CPOX-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2023

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: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786205053; hg19: chr3-98312217;