rs368528528

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000297770.10(CPA6):​c.1087G>A​(p.Gly363Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G363A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

CPA6
ENST00000297770.10 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.54
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CPA6NM_020361.5 linkuse as main transcriptc.1087G>A p.Gly363Arg missense_variant 10/11 ENST00000297770.10 NP_065094.3
ARFGEF1-DTNR_136224.1 linkuse as main transcriptn.470-14124C>T intron_variant, non_coding_transcript_variant
CPA6XM_017013646.2 linkuse as main transcriptc.643G>A p.Gly215Arg missense_variant 10/11 XP_016869135.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CPA6ENST00000297770.10 linkuse as main transcriptc.1087G>A p.Gly363Arg missense_variant 10/111 NM_020361.5 ENSP00000297770 P1Q8N4T0-1

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000945
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251198
Hom.:
1
AF XY:
0.0000737
AC XY:
10
AN XY:
135772
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000579
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:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000465
AC:
68
AN:
1461130
Hom.:
1
Cov.:
28
AF XY:
0.0000523
AC XY:
38
AN XY:
726922
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.0000459
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000145
AC:
22
AN:
152090
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74296
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000945
Gnomad4 NFE
AF:
0.000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000410
Hom.:
0
Bravo
AF:
0.0000529
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000741
AC:
9
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Febrile seizures, familial, 11 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 01, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 472759). This variant has not been reported in the literature in individuals affected with CPA6-related conditions. This variant is present in population databases (rs368528528, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 363 of the CPA6 protein (p.Gly363Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.061
T
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.059
T
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.082
D
MetaRNN
Pathogenic
0.82
D
MetaSVM
Benign
-0.57
T
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-2.5
D
REVEL
Uncertain
0.40
Sift
Benign
0.19
T
Sift4G
Benign
0.25
T
Polyphen
1.0
D
Vest4
0.91
MutPred
0.76
Gain of MoRF binding (P = 0.0037);
MVP
0.67
MPC
0.25
ClinPred
0.57
D
GERP RS
5.4
Varity_R
0.37
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368528528; hg19: chr8-68340321; COSMIC: COSV105132153; API