Variant 4-165464443-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000402744.9(CPE):c.361C>T(p.Arg121Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,064 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CPE
ENST00000402744.9 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.73

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-165464443-C-T is Pathogenic according to our data. Variant chr4-165464443-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1209851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-165464443-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPE	NM_001873.4 linkuse as main transcript	c.361C>T	p.Arg121Ter	stop_gained	2/9	ENST00000402744.9	NP_001864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPE	ENST00000402744.9 linkuse as main transcript	c.361C>T	p.Arg121Ter	stop_gained	2/9	1	NM_001873.4	ENSP00000386104	P1	P16870-1
CPE	ENST00000511992.1 linkuse as main transcript	c.25C>T	p.Arg9Ter	stop_gained	2/5	5		ENSP00000423699
CPE	ENST00000431967.5 linkuse as main transcript	c.25C>T	p.Arg9Ter	stop_gained	2/4	4		ENSP00000416601
CPE	ENST00000513982.5 linkuse as main transcript	c.25C>T	p.Arg9Ter	stop_gained	2/4	4		ENSP00000424830

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250442

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135356

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461064

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726818

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

BDV syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2021	- -

Blakemore-Durmaz-Vasileiou (BDV) syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Jun 16, 2021

The homozygous variant c.[361C > T]; c.[361C > T]; p.[Arg121*]; [(Arg121*)] was identified in two Syrian siblings and in one individual of Egypt origin. Parental consanguinity in both families present. All individuals show developmental delay, obesity, hyperphagia, suspected hypogonadotrophic hypogonadism and hypothyreoidism. The nonsense-variant p.(Arg121*) occurs in the catalytic domain of CPE. No homozygosity for truncating LoF variants in the general population database gnomAD (Genome Aggregation Database) has been listed to date. This variant was reported in heterozygous state one time in gnomAD. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.87

MutationTaster

Benign

1.0

Vest4

0.99

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 27

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