rs183899632
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_020361.5(CPA6):c.107G>T(p.Arg36Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
CPA6
NM_020361.5 missense
NM_020361.5 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 3.96
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 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25859475).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CPA6 | NM_020361.5 | c.107G>T | p.Arg36Leu | missense_variant | 1/11 | ENST00000297770.10 | NP_065094.3 | |
CPA6 | XM_017013647.2 | c.107G>T | p.Arg36Leu | missense_variant | 1/7 | XP_016869136.1 | ||
CPA6 | XM_017013646.2 | c.-300G>T | 5_prime_UTR_variant | 1/11 | XP_016869135.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CPA6 | ENST00000297770.10 | c.107G>T | p.Arg36Leu | missense_variant | 1/11 | 1 | NM_020361.5 | ENSP00000297770.4 | ||
CPA6 | ENST00000479862.6 | n.107G>T | non_coding_transcript_exon_variant | 1/8 | 1 | ENSP00000419016.2 | ||||
CPA6 | ENST00000518549.1 | n.321G>T | non_coding_transcript_exon_variant | 1/8 | 1 | |||||
CPA6 | ENST00000638254.1 | n.107G>T | non_coding_transcript_exon_variant | 1/10 | 5 | ENSP00000491129.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152070Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000558 AC: 14AN: 250678Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135482
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GnomAD4 exome AF: 0.0000164 AC: 24AN: 1460282Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10AN XY: 726476
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74410
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial temporal lobe epilepsy 5;C3280734:Febrile seizures, familial, 11 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Aug 14, 2019 | The c.107G>T (p.Arg36Leu) variant identified it the CPA6 gene substitutes a moderately conserved Arginine for Leucine at amino acid 36. This variant is found in gnomAD (15 heterozygotes, 0 homozygotes; allele frequency: 5.32e-5) and ExAC (5 heterozygotes, 0 homozygotes; allele frequency: 4.18e-5). In silico algorithms predict this variant to be Neutral (Provean; score: -2.36) and Damaging (SIFT; score: 0.013) to the function of the canonical transcript. This variant is classified in ClinVar as a Varaint of Uncertain Significance (VarID: 569405), and while the c.107G>T (p.Arg36Leu) variant identified in this individual has never been reported in the literature, a different change at the same nucleotide has been reported. A c.107G>A (p.Arg36His) variant in the CPA6 gene was reported in a female with Juvenile Myoclonic Epilepsy [PMID: 25875328]. The reported patient was described with myoclonic seizures, generalized tonic-clonic seizures, and absence seizures that were onset at 16.5 years of age. Functional studies on the p.Arg36His variant demonstrated 50% reduction of the mutant protein in the extracellular matrix [PMID: 25875328]. While a variant at the same nucleotide has been reported in an individual affected with epilepsy, the lack of functional data or additional evidence supporting the pathogenicity for the c.107G>T (p.Arg36Leu) variant identified in this patient results in its report here as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 04, 2021 | - - |
Febrile seizures, familial, 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 02, 2022 | In 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CPA6 protein function. ClinVar contains an entry for this variant (Variation ID: 569405). This variant has not been reported in the literature in individuals affected with CPA6-related conditions. This variant is present in population databases (rs183899632, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 36 of the CPA6 protein (p.Arg36Leu). - |
Familial temporal lobe epilepsy 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 30, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
PrimateAI
Benign
T
PROVEAN
Uncertain
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
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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