rs121917866

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000097.7(CPOX):c.991C>T(p.Arg331Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CPOX
NM_000097.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 3.28

Publications

6 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:

ENSG00000285635 (HGNC:):

ENSG00000285635 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000097.7

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7 link	c.991C>T	p.Arg331Trp	missense_variant	Exon 5 of 7	ENST00000647941.2	NP_000088.3	P36551-1
CPOX	XM_005247125.5 link	c.991C>T	p.Arg331Trp	missense_variant	Exon 5 of 6		XP_005247182.1
CPOX	XR_001740025.3 link	n.1098C>T		non_coding_transcript_exon_variant	Exon 5 of 7
CPOX	XM_047447473.1 link	c.*596C>T		downstream_gene_variant			XP_047303429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPOX	ENST00000647941.2 link	c.991C>T	p.Arg331Trp	missense_variant	Exon 5 of 7		NM_000097.7	ENSP00000497326.1	P36551-1
CPOX	ENST00000510489.1 link	n.241C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
ENSG00000285635	ENST00000512905.6 link	n.-126C>T		upstream_gene_variant		5		ENSP00000425880.1	H0YA22

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251432

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111906

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Coproporphyria

Pathogenic:1

May 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hereditary coproporphyria

Uncertain:1

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

D;D

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

1.0

D;.

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

3.3

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.9

D;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.016

D;.

Sift4G

Uncertain

0.028

D;.

Polyphen

1.0

D;D

Vest4

0.87

MutPred

0.84

Loss of disorder (P = 0.0421);Loss of disorder (P = 0.0421);

MVP

0.99

MPC

1.5

ClinPred

0.99

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.78

gMVP

0.72

Mutation Taster

=62/38

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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