Genetic Variant CPN1:p.His433His (chr10-100042505-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.1299C>T(p.His433His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,613,770 control chromosomes in the GnomAD database, including 1,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.029 ( 77 hom., cov: 31)

Exomes 𝑓: 0.035 ( 994 hom. )

Consequence

CPN1
NM_001308.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -4.38

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=-0.91).

BP6

Variant 10-100042505-G-A is Benign according to our data. Variant chr10-100042505-G-A is described in ClinVar as [Benign]. Clinvar id is 3344721.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-4.38 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPN1	NM_001308.3 link	c.1299C>T	p.His433His	synonymous_variant	Exon 9 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.1299C>T	p.His433His	synonymous_variant	Exon 9 of 9	1	NM_001308.3	ENSP00000359446.3		P15169

Frequencies

GnomAD3 genomes

AF:

0.0288

AC:

4373

AN:

151834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00733

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.0473

Gnomad ASJ

AF:

0.0303

Gnomad EAS

AF:

0.0239

Gnomad SAS

AF:

0.0133

Gnomad FIN

AF:

0.0402

Gnomad MID

AF:

0.0382

Gnomad NFE

AF:

0.0372

Gnomad OTH

AF:

0.0402

GnomAD3 exomes

AF:

0.0356

AC:

8932

AN:

251206

Hom.:

178

AF XY:

0.0347

AC XY:

4710

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00707

Gnomad AMR exome

AF:

0.0620

Gnomad ASJ exome

AF:

0.0278

Gnomad EAS exome

AF:

0.0259

Gnomad SAS exome

AF:

0.0110

Gnomad FIN exome

AF:

0.0420

Gnomad NFE exome

AF:

0.0390

Gnomad OTH exome

AF:

0.0395

GnomAD4 exome

AF:

0.0352

AC:

51491

AN:

1461818

Hom.:

994

Cov.:

AF XY:

0.0348

AC XY:

25323

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00654

Gnomad4 AMR exome

AF:

0.0583

Gnomad4 ASJ exome

AF:

0.0295

Gnomad4 EAS exome

AF:

0.0286

Gnomad4 SAS exome

AF:

0.0120

Gnomad4 FIN exome

AF:

0.0403

Gnomad4 NFE exome

AF:

0.0371

Gnomad4 OTH exome

AF:

0.0323

GnomAD4 genome

AF:

0.0288

AC:

4373

AN:

151952

Hom.:

Cov.:

AF XY:

0.0286

AC XY:

2124

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.00729

Gnomad4 AMR

AF:

0.0474

Gnomad4 ASJ

AF:

0.0303

Gnomad4 EAS

AF:

0.0239

Gnomad4 SAS

AF:

0.0131

Gnomad4 FIN

AF:

0.0402

Gnomad4 NFE

AF:

0.0372

Gnomad4 OTH

AF:

0.0398

Alfa

AF:

0.0329

Hom.:

Bravo

AF:

0.0296

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0437

EpiControl

AF:

0.0449

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CPN1-related disorder

Benign:1

Jul 08, 2024

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

-0.91

CADD

Benign

0.077

DANN

Benign

0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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