4-165464443-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001873.4(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 NM_001873.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.73

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]

ACMG classification

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	UniProt
CPE	NM_001873.4	c.361C>T	p.Arg121Ter	stop_gained	2/9	ENST00000402744.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPE	ENST00000402744.9	c.361C>T	p.Arg121Ter	stop_gained	2/9	1	NM_001873.4	P1
CPE	ENST00000511992.1	c.25C>T	p.Arg9Ter	stop_gained	2/5	5
CPE	ENST00000431967.5	c.25C>T	p.Arg9Ter	stop_gained	2/4	4
CPE	ENST00000513982.5	c.25C>T	p.Arg9Ter	stop_gained	2/4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250442 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135356

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: 2 AN: 1461064 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726818

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A
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

Other links and lift over

dbSNP: rs1317332155; hg19: chr4-166385595;