10-100065197-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001308.3(CPN1):c.750C>T(p.Leu250=) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.044 (264 hom., cov: 32)
  • Exomes 𝑓: 0.021 (682 hom.)
• Consequence: CPN1 NM_001308.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.143

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]

ACMG classification

Verdict is Benign. Variant got -15 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 criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
CPN1	NM_001308.3	c.750C>T	p.Leu250=	synonymous_variant	4/9	ENST00000370418.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPN1	ENST00000370418.8	c.750C>T	p.Leu250=	synonymous_variant	4/9	1	NM_001308.3	P1
CPN1	ENST00000441382.1	c.141C>T	p.Leu47=	synonymous_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.0441 AC: 6713 AN: 152120 Hom.: 255 Cov.: 32

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

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.: 31 AF XY: 0.0221 AC XY: 16032 AN XY: 726494

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.: 32 AF XY: 0.0441 AC XY: 3280 AN XY: 74446

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.: 66

Bravo AF: 0.0463

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CPN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2019

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

Other links and lift over

dbSNP: rs3750717; hg19: chr10-101824954;