rs61751507

Variant names:

• chr10-100069757-C-T
• rs61751507
• NM_001308.3:c.533G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 6.17
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• carboxypeptidase N deficiency

  Inheritance: AR Classification: LIMITED Submitted by: Illumina, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053716004).
• BP6: Variant 10-100069757-C-T is Benign according to our data. Variant chr10-100069757-C-T is described in ClinVar as Benign. ClinVar VariationId is 6623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPN1	NM_001308.3	MANE Select	c.533G>A	p.Gly178Asp	missense	Exon 3 of 9	NP_001299.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPN1	ENST00000370418.8	TSL:1 MANE Select	c.533G>A	p.Gly178Asp	missense	Exon 3 of 9	ENSP00000359446.3

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5254 AN: 151744 Hom.: 131 Cov.: 31

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

GnomAD2 exomes AF: 0.0423 AC: 10647 AN: 251480 AF XY: 0.0420

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 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.: 32 AF XY: 0.0437 AC XY: 31788 AN XY: 727222

African (AFR) AF: 0.00824 AC: 276 AN: 33480

American (AMR) AF: 0.0632 AC: 2825 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 694 AN: 26136

East Asian (EAS) AF: 0.0245 AC: 971 AN: 39698

South Asian (SAS) AF: 0.0250 AC: 2159 AN: 86258

European-Finnish (FIN) AF: 0.0392 AC: 2095 AN: 53420

Middle Eastern (MID) AF: 0.0740 AC: 427 AN: 5768

European-Non Finnish (NFE) AF: 0.0470 AC: 52277 AN: 1111948

Other (OTH) AF: 0.0387 AC: 2336 AN: 60392

GnomAD4 genome AF: 0.0346 AC: 5255 AN: 151860 Hom.: 131 Cov.: 31 AF XY: 0.0335 AC XY: 2483 AN XY: 74202

African (AFR) AF: 0.00894 AC: 370 AN: 41404

American (AMR) AF: 0.0525 AC: 799 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3470

East Asian (EAS) AF: 0.0242 AC: 125 AN: 5160

South Asian (SAS) AF: 0.0299 AC: 143 AN: 4784

European-Finnish (FIN) AF: 0.0344 AC: 363 AN: 10564

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0479 AC: 3254 AN: 67960

Other (OTH) AF: 0.0452 AC: 95 AN: 2102

Alfa AF: 0.0436 Hom.: 257

Bravo AF: 0.0353

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0428 AC: 165

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0480 AC: 413

ExAC AF: 0.0418 AC: 5076

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.0546

EpiControl AF: 0.0552

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anaphylotoxin inactivator deficiency Pathogenic:1 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.32
Sift	Benign	0.17	T
Sift4G	Benign	0.33	T
Polyphen		0.86	P
Vest4		0.29
MPC		1.3
ClinPred		0.055	T
GERP RS		4.3
Varity_R		0.54
gMVP		0.94
Mutation Taster		=76/24	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61751507; hg19: chr10-101829514; COSMIC: COSV107465314; COSMIC: COSV107465314;