Variant 10-100069757-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001308.3(CPN1):c.533G>A(p.Gly178Asp) variant causes a missense change. The variant allele was found at a frequency of 0.043 in 1,613,682 control chromosomes in the GnomAD database, including 1,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 131 hom., cov: 31)

Exomes 𝑓: 0.044 ( 1536 hom. )

Consequence

CPN1
NM_001308.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:4

Conservation

PhyloP100: 6.17

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053716004).

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPN1	NM_001308.3 link	c.533G>A	p.Gly178Asp	missense_variant	Exon 3 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.533G>A	p.Gly178Asp	missense_variant	Exon 3 of 9	1	NM_001308.3	ENSP00000359446.3		P15169

Frequencies

GnomAD3 genomes

AF:

0.0346

AC:

5254

AN:

151744

Hom.:

131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00899

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0525

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.0242

Gnomad SAS

AF:

0.0297

Gnomad FIN

AF:

0.0344

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0479

Gnomad OTH

AF:

0.0456

GnomAD3 exomes

AF:

0.0423

AC:

10647

AN:

251480

Hom.:

255

AF XY:

0.0420

AC XY:

5711

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00910

Gnomad AMR exome

AF:

0.0669

Gnomad ASJ exome

AF:

0.0250

Gnomad EAS exome

AF:

0.0243

Gnomad SAS exome

AF:

0.0242

Gnomad FIN exome

AF:

0.0400

Gnomad NFE exome

AF:

0.0492

Gnomad OTH exome

AF:

0.0450

GnomAD4 exome

AF:

0.0438

AC:

64060

AN:

1461822

Hom.:

1536

Cov.:

AF XY:

0.0437

AC XY:

31788

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00824

Gnomad4 AMR exome

AF:

0.0632

Gnomad4 ASJ exome

AF:

0.0266

Gnomad4 EAS exome

AF:

0.0245

Gnomad4 SAS exome

AF:

0.0250

Gnomad4 FIN exome

AF:

0.0392

Gnomad4 NFE exome

AF:

0.0470

Gnomad4 OTH exome

AF:

0.0387

GnomAD4 genome

AF:

0.0346

AC:

5255

AN:

151860

Hom.:

131

Cov.:

AF XY:

0.0335

AC XY:

2483

AN XY:

74202

show subpopulations

Gnomad4 AFR

AF:

0.00894

Gnomad4 AMR

AF:

0.0525

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.0242

Gnomad4 SAS

AF:

0.0299

Gnomad4 FIN

AF:

0.0344

Gnomad4 NFE

AF:

0.0479

Gnomad4 OTH

AF:

0.0452

Alfa

AF:

0.0463

Hom.:

176

Bravo

AF:

0.0353

TwinsUK

AF:

0.0464

AC:

172

ALSPAC

AF:

0.0428

AC:

165

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.0480

AC:

413

ExAC

AF:

0.0418

AC:

5076

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0546

EpiControl

AF:

0.0552

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anaphylotoxin inactivator deficiency

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2003	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all):461/13006=3.54% -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

CPN1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2024

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

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

0.16

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.32

Sift

Benign

0.17

Sift4G

Benign

0.33

Polyphen

0.86

Vest4

0.29

MPC

1.3

ClinPred

0.055

GERP RS

4.3

Varity_R

0.54

gMVP

0.94

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