8-67483807-C-T

Variant names:

• chr8-67483807-C-T
• rs61738009
• NM_020361.5:c.799G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP3 BP4_Moderate BS2

The NM_020361.5(CPA6):​c.799G>A​(p.Gly267Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,614,204 control chromosomes in the GnomAD database, including 9 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 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (9 hom.)
• Consequence: CPA6 NM_020361.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:9 B:3
• Conservation: PhyloP100: 7.47

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]

ARFGEF1-DT (HGNC:55237): (ARFGEF1 divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a disulfide_bond (size 23) in uniprot entity CBPA6_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_020361.5
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.13679942).
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA6	NM_020361.5	c.799G>A	p.Gly267Arg	missense_variant	Exon 8 of 11	ENST00000297770.10	NP_065094.3
CPA6	XM_017013646.2	c.355G>A	p.Gly119Arg	missense_variant	Exon 8 of 11		XP_016869135.1
ARFGEF1-DT	NR_136224.1	n.694-7158C>T		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPA6	ENST00000297770.10	c.799G>A	p.Gly267Arg	missense_variant	Exon 8 of 11	1	NM_020361.5	ENSP00000297770.4

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00313

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00202 AC: 509 AN: 251470 Hom.: 0 AF XY: 0.00205 AC XY: 278 AN XY: 135902

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00291 AC: 4248 AN: 1461872 Hom.: 9 Cov.: 30 AF XY: 0.00283 AC XY: 2055 AN XY: 727240

Gnomad4 AFR exome AF: 0.00329

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00343

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00249 AC: 380 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74496

Gnomad4 AFR AF: 0.00320

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00313

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00293 Hom.: 3

Bravo AF: 0.00283

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00211 AC: 256

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00462

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial temporal lobe epilepsy 5 Pathogenic:1 Uncertain:2

Dec 14, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 01, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:3

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in two unrelated individuals with temporal lobe epilepsy who were not reported to harbor the Q207E variant and had no detectable mutant protein in the extracellular matrix where wild-type enzyme is typically observed (Salzmann et al., 2012); Reported in an individual with temporal lobe epilepsy who was also heterozygous for the Q207E variant, but familial segregation information was not included (Sapio et al., 2012; Salzmann et al., 2012); Reported in cis with Q207E 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); 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: 23105115, 26648591, 32581362, 33096746, 28761347, 29358611, 21922598) -

not specified Uncertain:1 Benign:1

Jan 03, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CPA6 c.799G>A (p.Gly267Arg) results in a non-conservative amino acid change located in the peptidase M14, carboxypeptidase A domain (IPR000834) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 1614204 control chromosomes, predominantly at a frequency of 0.0034 within the African or African-American subpopulation in the gnomAD database (v4.1.0), including 8 homozygotes. c.799G>A has been reported in the literature in heterozygous individuals affected with temporal lobe epilepsy (Salzmann_2012). It has also been reported to co-occur with another CPA6 missense variant, p.Gln207Glu, either in cis or phase unknown, in patients with CPA6-Related Disorders (e.g. Sapio_2012, Muona_2015, van Eyk_2021, Bobbili_2018, Allen_2016, Sanchis-Juan_2023, Coppola_2024). These report(s) 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. The most pronounced variant effect results in <10% of normal carboxypeptidase activity in transfected cells (Salzmann_2012, Sapio_2012). The following publications have been ascertained in the context of this evaluation (PMID: 26648591, 29358611, 38088023, 25401298, 21922598, 37541188, 23105115, 34531397). ClinVar contains an entry for this variant (Variation ID: 281269). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Febrile seizures, familial, 11 Benign:2

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Molecular Genetics Lab, CHRU Brest

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Self-limited epilepsy with centrotemporal spikes Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

CAADphred>15 -

Confusion;C0030252:Palpitations;C0036572:Seizure;C0156404:Irregular menstruation;C0751495:Focal-onset seizure;C4020949:Abnormal emotional state;C5399973:Periventricular heterotopia Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Global developmental delay Uncertain:1

Feb 21, 2017

Claritas Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CPA6-related disorder Uncertain:1

Mar 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CPA6 c.799G>A variant is predicted to result in the amino acid substitution p.Gly267Arg. This variant is documented in the gnomAD general population database at a frequency inconsistent with autosomal dominant inheritance. However, it has been reported in the heterozygous state in 3 unrelated patients with temporal lobe epilepsy. One of the patients was heterozygous for a second variant of uncertain significance with unknown phase (Subject ET 158, p.Gln207Glu, Salzmann et al. 2012. PubMed ID: 21922598; Sapio et al. 2012. PubMed ID: 23105115). In another study, p.Gly267Arg and p.Gln207Glu were detected in cis, in a proband with developmental and epileptic encephalopathy who inherited the haplotype from his mother with unexplained epilepsy (Allen NM et al 2015. PubMed ID: 26648591). In vitro functional studies in an overexpression system have indicated that the p.Gly267Arg missense variant causes a strong reduction of protein level and carboxypeptidase activity, leading the authors to speculate that it may be pathogenic for recessive disease (Sapio et al. 2012. PubMed ID: 23105115). Taken together, due to conflicting genetic and functional evidence, the clinical significance of this variant is uncertain at this time. -

Familial temporal lobe epilepsy 5;C3280734:Febrile seizures, familial, 11 Uncertain:1

Jun 21, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inherited missense variant c.799G>A (p.Gly267Arg) in the CPA6 gene has been reported in the literature in individuals affected with epilepsy [PMIDs: 21922598, 23105115, 26648591]. This variant has been reported as heterozygous in two unrelated individuals affected with temporal lobe epilepsy [PMID:21922598]. The c.799G>A (p.Gly267Arg) variant has 0.002496 allele frequency in the gnomAD(v3) database (380 out of 152214 heterozygous alleles, no homozygotes). This variant affects evolutionarily conserved residues and is predicted deleterious by multiple in silico prediction tools. In vitro functional expression studies in cellular assays suggest that this 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 variant c.799G>A (p.Gly267Arg)] 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.1	H
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.88		Gain of disorder (P = 0.0488);
MVP		0.86
MPC		0.25
ClinPred		0.16	T
GERP RS		5.2
Varity_R		0.95
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61738009; hg19: chr8-68396042; COSMIC: COSV99913488;