rs786205053

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_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

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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

CPOX-related hereditary coproporphyria
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
hereditary coproporphyria
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
harderoporphyria
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp

CPOX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 3-98593373-G-GGCTGC is Pathogenic according to our data. Variant chr3-98593373-G-GGCTGC is described in ClinVar as Pathogenic. ClinVar VariationId is 454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7 link	c.127_131dupGCAGC	p.Gly45GlnfsTer93	frameshift_variant	Exon 1 of 7	ENST00000647941.2	NP_000088.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CPOX	ENST00000647941.2 link	c.127_131dupGCAGC	p.Gly45GlnfsTer93	frameshift_variant	Exon 1 of 7		NM_000097.7	ENSP00000497326.1
CPOX	ENST00000513674.1 link	n.127_131dupGCAGC		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000424924.1
CPOX	ENST00000515041.1 link	n.233_237dupGCAGC		non_coding_transcript_exon_variant	Exon 1 of 3	2

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

African (AFR)

AF:

0.00

AC:

AN:

23494

American (AMR)

AF:

0.00

AC:

AN:

9456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16230

East Asian (EAS)

AF:

0.00

AC:

AN:

27204

South Asian (SAS)

AF:

0.0000451

AC:

AN:

44358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3368

European-Non Finnish (NFE)

AF:

0.00000302

AC:

AN:

992508

Other (OTH)

AF:

0.00

AC:

AN:

49172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151930

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41408

American (AMR)

AF:

0.0000655

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67958

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Dec 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 14, 2016

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

CPOX-related disorder

Pathogenic:1

May 03, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

PhyloP100

2.2

Mutation Taster

=7/193

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over