Genetic Variant CPA6:p.Val42Gly (chr8-67624243-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020361.5(CPA6):c.125T>G(p.Val42Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000762 in 1,311,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V42A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

CPA6
NM_020361.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.26

Publications

0 publications found

Variant links:

Genes affected

CPA6 (HGNC:17245): (carboxypeptidase A6) The gene encodes a member of the peptidase M14 family of metallocarboxypeptidases. The encoded preproprotein is proteolytically processed to generate the mature enzyme, which catalyzes the release of large hydrophobic C-terminal amino acids. This enzyme has functions ranging from digestion of food to selective biosynthesis of neuroendocrine peptides. Mutations in this gene may be linked to epilepsy and febrile seizures, and a translocation t(6;8)(q26;q13) involving this gene has been associated with Duane retraction syndrome. [provided by RefSeq, May 2016]

CPA6 Gene-Disease associations (from GenCC):

benign familial mesial temporal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial mesial temporal lobe epilepsy with febrile seizures
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial temporal lobe epilepsy 5
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
febrile seizures, familial, 11
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
epilepsy
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

CPA6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA6	NM_020361.5 link	c.125T>G	p.Val42Gly	missense_variant	Exon 2 of 11	ENST00000297770.10	NP_065094.3	Q8N4T0-1
CPA6	NM_001440615.1 link	c.125T>G	p.Val42Gly	missense_variant	Exon 2 of 7		NP_001427544.1
CPA6	XM_017013646.2 link	c.-195T>G		5_prime_UTR_variant	Exon 3 of 11		XP_016869135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPA6	ENST00000297770.10 link	c.125T>G	p.Val42Gly	missense_variant	Exon 2 of 11	1	NM_020361.5	ENSP00000297770.4	Q8N4T0-1
CPA6	ENST00000479862.6 link	n.125T>G		non_coding_transcript_exon_variant	Exon 2 of 8	1		ENSP00000419016.2	Q8N4T0-3
CPA6	ENST00000518549.1 link	n.339T>G		non_coding_transcript_exon_variant	Exon 2 of 8	1
CPA6	ENST00000638254.1 link	n.125T>G		non_coding_transcript_exon_variant	Exon 2 of 10	5		ENSP00000491129.1	Q8N4T0-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.62e-7

AC:

AN:

1311788

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

659878

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:

29908

American (AMR)

AF:

0.00

AC:

AN:

42010

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25076

East Asian (EAS)

AF:

0.00

AC:

AN:

38954

South Asian (SAS)

AF:

0.00

AC:

AN:

80794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5456

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

981242

Other (OTH)

AF:

0.00

AC:

AN:

55430

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.57

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.0

PhyloP100

4.3

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.65

MutPred

0.79

Loss of stability (P = 0.0176);

MVP

0.81

MPC

0.20

ClinPred

0.99

GERP RS

5.4

Varity_R

0.94

gMVP

0.89

Mutation Taster

=220/80

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over