Genetic Variant CPN1:p.Leu250Leu (chr10-100065197-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_001308.3(CPN1):c.750C>T(p.Leu250Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,613,040 control chromosomes in the GnomAD database, including 946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.044 ( 264 hom., cov: 32)

Exomes 𝑓: 0.021 ( 682 hom. )

Consequence

CPN1
NM_001308.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.143

Variant links:

Genes affected

CPN1 (HGNC:2312): (carboxypeptidase N subunit 1) Carboxypeptidase N is a plasma metallo-protease that cleaves basic amino acids from the C terminal of peptides and proteins. The enzyme is important in the regulation of peptides like kinins and anaphylatoxins, and has also been known as kininase-1 and anaphylatoxin inactivator. This enzyme is a tetramer comprised of two identical regulatory subunits and two identical catalytic subunits; this gene encodes the catalytic subunit. Mutations in this gene can be associated with angioedema or chronic urticaria resulting from carboxypeptidase N deficiency. [provided by RefSeq, Jul 2008]

CPN1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 10-100065197-G-A is Benign according to our data. Variant chr10-100065197-G-A is described in ClinVar as [Benign]. Clinvar id is 3055820.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.143 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPN1	NM_001308.3 link	c.750C>T	p.Leu250Leu	synonymous_variant	Exon 4 of 9	ENST00000370418.8	NP_001299.1	P15169

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPN1	ENST00000370418.8 link	c.750C>T	p.Leu250Leu	synonymous_variant	Exon 4 of 9	1	NM_001308.3	ENSP00000359446.3		P15169
CPN1	ENST00000441382.1 link	c.141C>T	p.Leu47Leu	synonymous_variant	Exon 1 of 5	2		ENSP00000410895.1		B1AP58

Frequencies

GnomAD3 genomes

AF:

0.0441

AC:

6713

AN:

152120

Hom.:

255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.0624

Gnomad SAS

AF:

0.0581

Gnomad FIN

AF:

0.0205

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.0392

GnomAD3 exomes

AF:

0.0315

AC:

7881

AN:

249952

Hom.:

218

AF XY:

0.0314

AC XY:

4254

AN XY:

135264

show subpopulations

Gnomad AFR exome

AF:

0.107

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.0631

Gnomad SAS exome

AF:

0.0568

Gnomad FIN exome

AF:

0.0226

Gnomad NFE exome

AF:

0.0169

Gnomad OTH exome

AF:

0.0339

GnomAD4 exome

AF:

0.0214

AC:

31214

AN:

1460802

Hom.:

682

Cov.:

AF XY:

0.0221

AC XY:

16032

AN XY:

726494

show subpopulations

Gnomad4 AFR exome

AF:

0.108

Gnomad4 AMR exome

AF:

0.0145

Gnomad4 ASJ exome

AF:

0.0244

Gnomad4 EAS exome

AF:

0.0547

Gnomad4 SAS exome

AF:

0.0532

Gnomad4 FIN exome

AF:

0.0244

Gnomad4 NFE exome

AF:

0.0147

Gnomad4 OTH exome

AF:

0.0288

GnomAD4 genome

AF:

0.0443

AC:

6745

AN:

152238

Hom.:

264

Cov.:

AF XY:

0.0441

AC XY:

3280

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.106

Gnomad4 AMR

AF:

0.0188

Gnomad4 ASJ

AF:

0.0216

Gnomad4 EAS

AF:

0.0622

Gnomad4 SAS

AF:

0.0577

Gnomad4 FIN

AF:

0.0205

Gnomad4 NFE

AF:

0.0156

Gnomad4 OTH

AF:

0.0388

Alfa

AF:

0.0294

Hom.:

Bravo

AF:

0.0463

Asia WGS

AF:

0.0620

AC:

216

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CPN1-related disorder

Benign:1

Dec 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.1

DANN

Benign

0.67

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