NM_001308.3:c.750C>T

Variant names:

• chr10-100065197-G-A
• rs3750717
• NM_001308.3:c.750C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001308.3(CPN1):​c.750C>T​(p.Leu250Leu) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.044 (264 hom., cov: 32)
  • Exomes 𝑓: 0.021 (682 hom.)
• Consequence: CPN1 NM_001308.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.143
• Publications: 10 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 -14 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 VariationId is 3055820.Status of the report is no_assertion_criteria_provided, 0 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPN1	NM_001308.3	MANE Select	c.750C>T	p.Leu250Leu	synonymous	Exon 4 of 9	NP_001299.1	P15169

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPN1	ENST00000370418.8	TSL:1 MANE Select	c.750C>T	p.Leu250Leu	synonymous	Exon 4 of 9	ENSP00000359446.3	P15169
	CPN1	ENST00000877014.1		c.689C>T	p.Ser230Phe	missense	Exon 4 of 9	ENSP00000547073.1
	CPN1	ENST00000877012.1		c.689C>T	p.Ser230Phe	missense	Exon 4 of 8	ENSP00000547071.1

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

GnomAD2 exomes AF: 0.0315 AC: 7881 AN: 249952 AF XY: 0.0314

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 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

African (AFR) AF: 0.108 AC: 3629 AN: 33450

American (AMR) AF: 0.0145 AC: 647 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0244 AC: 638 AN: 26120

East Asian (EAS) AF: 0.0547 AC: 2170 AN: 39672

South Asian (SAS) AF: 0.0532 AC: 4589 AN: 86202

European-Finnish (FIN) AF: 0.0244 AC: 1300 AN: 53368

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5760

European-Non Finnish (NFE) AF: 0.0147 AC: 16302 AN: 1111182

Other (OTH) AF: 0.0288 AC: 1739 AN: 60360

GnomAD4 genome AF: 0.0443 AC: 6745 AN: 152238 Hom.: 264 Cov.: 32 AF XY: 0.0441 AC XY: 3280 AN XY: 74446

African (AFR) AF: 0.106 AC: 4381 AN: 41516

American (AMR) AF: 0.0188 AC: 288 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.0622 AC: 322 AN: 5180

South Asian (SAS) AF: 0.0577 AC: 279 AN: 4832

European-Finnish (FIN) AF: 0.0205 AC: 217 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0156 AC: 1063 AN: 68028

Other (OTH) AF: 0.0388 AC: 82 AN: 2112

Alfa AF: 0.0300 Hom.: 68

Bravo AF: 0.0463

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CPN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.1
DANN	Benign	0.67
PhyloP100		-0.14
PromoterAI		-0.049	Neutral
Mutation Taster		=100/0	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: rs3750717; hg19: chr10-101824954;