dbSNP rs886058944: CPOX:c.*498_*499insCA (chr3-98580184-A-ATG) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000097.7(CPOX):c.*498_*499insCA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 986,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

CPOX
NM_000097.7 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.638

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

CPOX links:

ENSG00000285635 (HGNC:):

ENSG00000285635 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000097.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPOX	NM_000097.7	MANE Select	c.498_499insCA		3_prime_UTR	Exon 7 of 7	NP_000088.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CPOX	ENST00000647941.2	MANE Select	c.498_499insCA	3_prime_UTR	Exon 7 of 7	ENSP00000497326.1	P36551-1
ENSG00000285635	ENST00000512905.6	TSL:5	n.161+1222_161+1223insCA	intron	N/A	ENSP00000425880.1	H0YA22
CPOX	ENST00000946176.1		c.498_499insCA	3_prime_UTR	Exon 8 of 8	ENSP00000616235.1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000611

AC:

AN:

834146

Hom.:

Cov.:

AF XY:

0.0000519

AC XY:

AN XY:

385530

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

15702

American (AMR)

AF:

0.00

AC:

AN:

1600

Ashkenazi Jewish (ASJ)

AF:

0.00484

AC:

AN:

5162

East Asian (EAS)

AF:

0.00

AC:

AN:

3732

South Asian (SAS)

AF:

0.00

AC:

AN:

16818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1624

European-Non Finnish (NFE)

AF:

0.0000236

AC:

AN:

761774

Other (OTH)

AF:

0.000292

AC:

AN:

27360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.354

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:

0.000118

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000337

Hom.:

Bravo

AF:

0.000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary coproporphyria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.64

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over