NM_001308.3:c.918G>A

Variant names:

• chr10-100057106-C-T
• rs3750716
• NM_001308.3:c.918G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_001308.3(CPN1):​c.918G>A​(p.Thr306Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,614,142 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0019 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (34 hom.)
• Consequence: CPN1 NM_001308.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.22
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=-4.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00161 (2356/1461868) while in subpopulation AMR AF = 0.0353 (1578/44722). AF 95% confidence interval is 0.0338. There are 34 homozygotes in GnomAdExome4. There are 1039 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.918G>A	p.Thr306Thr	synonymous	Exon 6 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.918G>A	p.Thr306Thr	synonymous	Exon 6 of 9	ENSP00000359446.3	P15169
	CPN1	ENST00000877015.1		c.918G>A	p.Thr306Thr	synonymous	Exon 6 of 9	ENSP00000547074.1
	CPN1	ENST00000877014.1		c.906G>A	p.Thr302Thr	synonymous	Exon 6 of 9	ENSP00000547073.1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152156 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00982

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00659 AC: 1657 AN: 251458 AF XY: 0.00507

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0125

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00161 AC: 2356 AN: 1461868 Hom.: 34 Cov.: 32 AF XY: 0.00143 AC XY: 1039 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0353 AC: 1578 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0153 AC: 606 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111996

Other (OTH) AF: 0.00137 AC: 83 AN: 60394

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152274 Hom.: 5 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74456

African (AFR) AF: 0.000313 AC: 13 AN: 41534

American (AMR) AF: 0.0143 AC: 218 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00984 AC: 51 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68034

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000909 Hom.: 5

Bravo AF: 0.00411

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.045
DANN	Benign	0.77
PhyloP100		-4.2
Mutation Taster		=97/3	polymorphism

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: rs3750716; hg19: chr10-101816863; COSMIC: COSV64942323;