8-67506804-G-C

Position:

chr8-67506804-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_020361.5(CPA6):c.619C>G(p.Gln207Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,611,506 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

CPA6
NM_020361.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:9B:2

Conservation

PhyloP100: 8.97

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CPA6	NM_020361.5 linkuse as main transcript	c.619C>G	p.Gln207Glu	missense_variant	6/11	ENST00000297770.10	NP_065094.3
CPA6	XM_017013646.2 linkuse as main transcript	c.175C>G	p.Gln59Glu	missense_variant	6/11		XP_016869135.1
CPA6	XM_017013647.2 linkuse as main transcript	c.619C>G	p.Gln207Glu	missense_variant	6/7		XP_016869136.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPA6	ENST00000297770.10 linkuse as main transcript	c.619C>G	p.Gln207Glu	missense_variant	6/11	1	NM_020361.5	ENSP00000297770	P1	Q8N4T0-1
CPA6	ENST00000518549.1 linkuse as main transcript	n.833C>G		non_coding_transcript_exon_variant	6/8	1
CPA6	ENST00000479862.6 linkuse as main transcript	c.*215C>G		3_prime_UTR_variant, NMD_transcript_variant	5/8	1		ENSP00000419016		Q8N4T0-3
CPA6	ENST00000638254.1 linkuse as main transcript	c.*215C>G		3_prime_UTR_variant, NMD_transcript_variant	5/10	5		ENSP00000491129		Q8N4T0-3

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

186

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00219

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00146

AC:

366

AN:

251082

Hom.:

AF XY:

0.00153

AC XY:

207

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00244

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00206

AC:

3001

AN:

1459214

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

1466

AN XY:

726034

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00210

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00248

Gnomad4 OTH exome

AF:

0.00186

GnomAD4 genome

AF:

0.00122

AC:

186

AN:

152292

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00219

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00163

Hom.:

Bravo

AF:

0.00124

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00147

AC:

179

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 06, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2021	Reported in cis with G267R in an individual with early onset epileptic encephalopathy, inherited from the individual's mother who was reported to have unexplained epilepsy but not epileptic encephalopathy (Allen et al., 2016) Reported in an individual with temporal lobe epilepsy who was also heterozygous for the G267R variant, but familial segregation information was not included (Sapio et al., 2012) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function This variant is associated with the following publications: (PMID: 32581362, 29358611, 23105115, 26648591) -

Familial temporal lobe epilepsy 5

Pathogenic:1Uncertain:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 14, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Febrile seizures, familial, 11

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	- -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Confusion;C0030252:Palpitations;C0036572:Seizure;C0156404:Irregular menstruation;C0751495:Focal-onset seizure;C4020949:Abnormal emotional state;C5399973:Periventricular heterotopia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Global developmental delay

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Claritas Genomics

Feb 21, 2017

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 15, 2024

Variant summary: CPA6 c.619C>G (p.Gln207Glu) results in a conservative amino acid change located in the Peptidase M14, carboxypeptidase A domain (IPR000834) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 1611506 control chromosomes in the gnomAD database, including 4 homozygotes, suggesting the variant could be benign. c.619C>G has been reported in the literature in individuals of heterozygous or unspecified genotype affected with neurodevelopmental disorders including focal or progressive myoclonic epilepsy, early onset epileptic encephalopathy, intellectual disability, cerebral palsy, or other unspecified neurodevelopmental disorder all without evidence of causality, often found in cis or unknown phase with c.799G>A, p.G267R (e.g. Sapio_2012, Muona_2014, Allen_2015, Moortgat_2018, vanEyk_2021, Sanchis-Juan_2023, Coppola_2023). These reports do not provide unequivocal conclusions about association of the variant with CPA6-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function showing severely reduced CPA6 activity and protein expression in vitro (e.g. Sapio_2012). The following publications have been ascertained in the context of this evaluation (PMID: 26648591, 38088023, 29180823, 25401298, 37541188, 23105115, 34531397). ClinVar contains an entry for this variant (Variation ID: 393467). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Familial temporal lobe epilepsy 5;C3280734:Febrile seizures, familial, 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 21, 2021

The inherited missense variant c.619C>G (p.Gln207Glu) in the CPA6 gene has been reported in the literature in individuals affected with epilepsy [PMIDs: 21922598, 23105115, 26648591]. The variant has 0.001222 allele frequency in the gnomAD(v3) database (186 out of 152174 heterozygous alleles, no homozygotes). It affects evolutionarily conserved residues and is predicted deleterious by multiple in silico prediction tools. In vitro functional expression studies in cellular assays suggest that the variant reduces the CPA6 enzymatic activity compared to wild type protein [PMIDs: 21922598, 23105115]. However, additional studies are needed to determine the clinical significance of this variant. Based on the available evidence, the inherited heterozygous missense variants [c.619C>G(p.Gln207Glu)identified in the CPA6 gene is reported as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.70

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.48

Sift

Uncertain

0.014

Sift4G

Uncertain

0.015

Polyphen

0.98

Vest4

0.91

MVP

0.39

MPC

0.16

ClinPred

0.040

GERP RS

5.3

Varity_R

0.82

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: 3

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