Genetic Variant CPN1:p.Thr306Thr (chr10-100057106-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BS1BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.22

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. gnomad4_exome 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 gnomad4_exome. There are 1039 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPN1	NM_001308.3 link	c.918G>A	p.Thr306Thr	synonymous_variant	Exon 6 of 9	ENST00000370418.8	NP_001299.1	P15169

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPN1	ENST00000370418.8 link	c.918G>A	p.Thr306Thr	synonymous_variant	Exon 6 of 9	1	NM_001308.3	ENSP00000359446.3		P15169
CPN1	ENST00000441382.1 link	c.309G>A	p.Thr103Thr	synonymous_variant	Exon 3 of 5	2		ENSP00000410895.1		B1AP58

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

294

AN:

152156

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00659

AC:

1657

AN:

251458

Hom.:

AF XY:

0.00507

AC XY:

689

AN XY:

135900

show subpopulations

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 SAS exome

AF:

0.000817

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.:

Cov.:

AF XY:

0.00143

AC XY:

1039

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0353

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0153

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00194

AC:

295

AN:

152274

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.0143

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00984

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000443

Hom.:

Bravo

AF:

0.00411

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.045

DANN

Benign

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over