rs151119622
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_020361.5(CPA6):āc.326T>Cā(p.Ile109Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000602 in 1,594,260 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00026 ( 0 hom., cov: 32)
Exomes š: 0.000040 ( 1 hom. )
Consequence
CPA6
NM_020361.5 missense
NM_020361.5 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 6.03
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=0.1445477).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPA6 | NM_020361.5 | c.326T>C | p.Ile109Thr | missense_variant | 4/11 | ENST00000297770.10 | |
CPA6 | XM_017013647.2 | c.326T>C | p.Ile109Thr | missense_variant | 4/7 | ||
CPA6 | XM_017013646.2 | c.-119T>C | 5_prime_UTR_variant | 4/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPA6 | ENST00000297770.10 | c.326T>C | p.Ile109Thr | missense_variant | 4/11 | 1 | NM_020361.5 | P1 | |
CPA6 | ENST00000518549.1 | n.540T>C | non_coding_transcript_exon_variant | 4/8 | 1 | ||||
CPA6 | ENST00000479862.6 | c.201T>C | p.His67= | synonymous_variant, NMD_transcript_variant | 3/8 | 1 | |||
CPA6 | ENST00000638254.1 | c.201T>C | p.His67= | synonymous_variant, NMD_transcript_variant | 3/10 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000263 AC: 40AN: 152220Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000639 AC: 16AN: 250452Hom.: 0 AF XY: 0.0000887 AC XY: 12AN XY: 135338
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GnomAD4 exome AF: 0.0000395 AC: 57AN: 1441922Hom.: 1 Cov.: 26 AF XY: 0.0000445 AC XY: 32AN XY: 718648
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GnomAD4 genome ? AF: 0.000256 AC: 39AN: 152338Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74498
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2022 | The c.326T>C (p.I109T) alteration is located in exon 4 (coding exon 4) of the CPA6 gene. This alteration results from a T to C substitution at nucleotide position 326, causing the isoleucine (I) at amino acid position 109 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Febrile seizures, familial, 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 18, 2018 | This sequence change replaces isoleucine with threonine at codon 109 of the CPA6 protein (p.Ile109Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs151119622, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CPA6-related disease. ClinVar contains an entry for this variant (Variation ID: 363611). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 22, 2021 | - - |
Familial temporal lobe epilepsy 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
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
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
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