4-165379436-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001873.4(CPE):c.215C>T(p.Ala72Val) variant causes a missense change. The variant allele was found at a frequency of 0.00153 in 1,610,356 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 19 hom. )

Consequence

CPE
NM_001873.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.12

Variant links:

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]

CPE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011004746).

BP6

Variant 4-165379436-C-T is Benign according to our data. Variant chr4-165379436-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1610581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00196 (298/152272) while in subpopulation NFE AF= 0.00388 (264/68004). AF 95% confidence interval is 0.0035. There are 5 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPE	NM_001873.4 link	c.215C>T	p.Ala72Val	missense_variant	Exon 1 of 9	ENST00000402744.9	NP_001864.1	P16870-1A0A384N679

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPE	ENST00000402744.9 link	c.215C>T	p.Ala72Val	missense_variant	Exon 1 of 9	1	NM_001873.4	ENSP00000386104.4	P16870-1
CPE	ENST00000513982.5 link	c.-30+18125C>T		intron_variant	Intron 1 of 3	4		ENSP00000424830.1	D6RF88
CPE	ENST00000480404.1 link	n.151C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00196

AC:

298

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00388

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00157

AC:

373

AN:

236920

Hom.:

AF XY:

0.00161

AC XY:

210

AN XY:

130426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000590

Gnomad ASJ exome

AF:

0.00185

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00294

Gnomad NFE exome

AF:

0.00270

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.00148

AC:

2165

AN:

1458084

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1161

AN XY:

725298

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00358

Gnomad4 NFE exome

AF:

0.00166

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00196

AC:

298

AN:

152272

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

144

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00255

Gnomad4 NFE

AF:

0.00388

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00261

Hom.:

Bravo

AF:

0.00111

ESP6500AA

AF:

0.000233

AC:

ESP6500EA

AF:

0.00131

AC:

ExAC

AF:

0.00163

AC:

196

Asia WGS

AF:

0.000867

AC:

AN:

3474

EpiCase

AF:

0.00234

EpiControl

AF:

0.000892

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CPE: BS2 -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CPE-related disorder

Benign:1

Sep 21, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

0.048

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

M_CAP

Benign

0.062

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.1

REVEL

Benign

0.17

Sift

Uncertain

0.021

Sift4G

Benign

0.17

Polyphen

0.13

Vest4

0.16

MVP

0.14

MPC

0.64

ClinPred

0.10

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over