10-100076007-C-G

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.324G>C(p.Arg108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00696 in 1,614,062 control chromosomes in the GnomAD database, including 636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.035 (314 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (322 hom.)
• Consequence: CPN1 NM_001308.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.970

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=-0.81).
• BP6: Variant 10-100076007-C-G is Benign according to our data. Variant chr10-100076007-C-G is described in ClinVar as [Benign]. Clinvar id is 3038291.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPN1	NM_001308.3	c.324G>C	p.Arg108=	synonymous_variant	2/9	ENST00000370418.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPN1	ENST00000370418.8	c.324G>C	p.Arg108=	synonymous_variant	2/9	1	NM_001308.3	P1

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5308 AN: 152066 Hom.: 308 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0307

GnomAD3 exomes AF: 0.00922 AC: 2318 AN: 251464 Hom.: 123 AF XY: 0.00678 AC XY: 922 AN XY: 135910

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.00598

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00651

GnomAD4 exome AF: 0.00404 AC: 5900 AN: 1461878 Hom.: 322 Cov.: 31 AF XY: 0.00348 AC XY: 2529 AN XY: 727242

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.00695

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.0100

GnomAD4 genome AF: 0.0350 AC: 5332 AN: 152184 Hom.: 314 Cov.: 32 AF XY: 0.0345 AC XY: 2565 AN XY: 74390

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0304

Alfa AF: 0.0109 Hom.: 26

Bravo AF: 0.0408

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000593

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

Jan 28, 2020

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	-0.81
Cadd	Benign	1.5
Dann	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61754515; hg19: chr10-101835764;