4-165467748-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001873.4(CPE):c.565C>T(p.Arg189Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
CPE
NM_001873.4 missense
NM_001873.4 missense
Scores
7
7
4
Clinical Significance
Conservation
PhyloP100: 1.99
Genes affected
CPE (HGNC:2303): (carboxypeptidase E) This gene encodes a member of the M14 family of metallocarboxypeptidases. The encoded preproprotein is proteolytically processed to generate the mature peptidase. This peripheral membrane protein cleaves C-terminal amino acid residues and is involved in the biosynthesis of peptide hormones and neurotransmitters, including insulin. This protein may also function independently of its peptidase activity, as a neurotrophic factor that promotes neuronal survival, and as a sorting receptor that binds to regulated secretory pathway proteins, including prohormones. Mutations in this gene are implicated in type 2 diabetes. [provided by RefSeq, Nov 2015]
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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, 0.818
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPE | NM_001873.4 | c.565C>T | p.Arg189Trp | missense_variant | 3/9 | ENST00000402744.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPE | ENST00000402744.9 | c.565C>T | p.Arg189Trp | missense_variant | 3/9 | 1 | NM_001873.4 | P1 | |
CPE | ENST00000511992.1 | c.229C>T | p.Arg77Trp | missense_variant | 3/5 | 5 | |||
CPE | ENST00000431967.5 | c.229C>T | p.Arg77Trp | missense_variant | 3/4 | 4 | |||
CPE | ENST00000513982.5 | c.229C>T | p.Arg77Trp | missense_variant | 3/4 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000528 AC: 8AN: 151584Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250994Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135666
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461480Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727054
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GnomAD4 genome ? AF: 0.0000527 AC: 8AN: 151696Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3AN XY: 74054
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
CPE-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 16, 2024 | The CPE c.565C>T variant is predicted to result in the amino acid substitution p.Arg189Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
0.97
.;D;.;.
Vest4
0.99
MVP
MPC
0.69
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