8-67483807-C-T
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4_ModerateBS2
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
NM_020361.5 missense
Scores
10
6
3
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPA6 | NM_020361.5 | c.799G>A | p.Gly267Arg | missense_variant | 8/11 | ENST00000297770.10 | |
ARFGEF1-DT | NR_136224.1 | n.694-7158C>T | intron_variant, non_coding_transcript_variant | ||||
CPA6 | XM_017013646.2 | c.355G>A | p.Gly119Arg | missense_variant | 8/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPA6 | ENST00000297770.10 | c.799G>A | p.Gly267Arg | missense_variant | 8/11 | 1 | NM_020361.5 | P1 | |
CPA6 | ENST00000518549.1 | n.1013G>A | non_coding_transcript_exon_variant | 8/8 | 1 | ||||
CPA6 | ENST00000479862.6 | c.*395G>A | 3_prime_UTR_variant, NMD_transcript_variant | 7/8 | 1 | ||||
CPA6 | ENST00000638254.1 | c.*395G>A | 3_prime_UTR_variant, NMD_transcript_variant | 7/10 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00250 AC: 380AN: 152214Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00202 AC: 509AN: 251470Hom.: 0 AF XY: 0.00205 AC XY: 278AN XY: 135902
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GnomAD4 exome AF: 0.00291 AC: 4248AN: 1461872Hom.: 9 Cov.: 30 AF XY: 0.00283 AC XY: 2055AN XY: 727240
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GnomAD4 genome AF: 0.00249 AC: 380AN: 152332Hom.: 0 Cov.: 32 AF XY: 0.00220 AC XY: 164AN XY: 74496
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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 | Eurofins Ntd Llc (ga) | May 25, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 06, 2018 | - - |
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 | GeneDx | Jan 04, 2021 | 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) - |
Familial temporal lobe epilepsy 5 Pathogenic:1Uncertain:2
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). 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 14, 2012 | - - |
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 | Invitae | Nov 15, 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 emotion;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 | - - |
CPA6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 03, 2023 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 21, 2021 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0488);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at