Variant rs786205053 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.23

Variant links:

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]

CPOX links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
CPOX	NM_000097.7 linkuse as main transcript	c.131_132insGCAGC	p.Gly45GlnfsTer93	frameshift_variant	1/7	ENST00000647941.2	NP_000088.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941.2 linkuse as main transcript	c.131_132insGCAGC	p.Gly45GlnfsTer93	frameshift_variant	1/7		NM_000097.7	ENSP00000497326	P1	P36551-1
CPOX	ENST00000515041.1 linkuse as main transcript	n.237_238insGCAGC		non_coding_transcript_exon_variant	1/3	2
CPOX	ENST00000513674.1 linkuse as main transcript	c.131_132insGCAGC	p.Gly45GlnfsTer93	frameshift_variant, NMD_transcript_variant	1/4	5		ENSP00000424924

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151930

Hom.:

Cov.:

show subpopulations

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:

AN:

1193606

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

579570

show subpopulations

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:

AN:

151930

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74216

show subpopulations

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

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over