Variant 3-194341226-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001080513.4(CPN2):c.1477G>A(p.Ala493Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

CPN2
NM_001080513.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.791

Variant links:

Genes affected

CPN2 (HGNC:2313): (carboxypeptidase N subunit 2) Predicted to be involved in regulation of catalytic activity. Located in blood microparticle and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

CPN2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.00684762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CPN2	NM_001080513.4 linkuse as main transcript	c.1477G>A	p.Ala493Thr	missense_variant	2/2	ENST00000323830.4	NP_001073982.3
CPN2	NM_001291988.2 linkuse as main transcript	c.1477G>A	p.Ala493Thr	missense_variant	2/2		NP_001278917.1
CPN2	XM_005269280.5 linkuse as main transcript	c.1477G>A	p.Ala493Thr	missense_variant	3/3		XP_005269337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPN2	ENST00000323830.4 linkuse as main transcript	c.1477G>A	p.Ala493Thr	missense_variant	2/2	1	NM_001080513.4	ENSP00000319464	P1
CPN2	ENST00000429275.1 linkuse as main transcript	c.1477G>A	p.Ala493Thr	missense_variant	2/2	5		ENSP00000402232	P1

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000918

AC:

230

AN:

250486

Hom.:

AF XY:

0.000877

AC XY:

119

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00667

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000279

Gnomad NFE exome

AF:

0.00112

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00114

AC:

1671

AN:

1461160

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

821

AN XY:

726916

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00613

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000417

Gnomad4 NFE exome

AF:

0.00122

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.000794

AC:

121

AN:

152378

Hom.:

Cov.:

AF XY:

0.000751

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000326

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00119

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00123

Hom.:

Bravo

AF:

0.000774

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000774

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.1477G>A (p.A493T) alteration is located in exon 2 (coding exon 1) of the CPN2 gene. This alteration results from a G to A substitution at nucleotide position 1477, causing the alanine (A) at amino acid position 493 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.59

.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

0.64

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.67

N;N

REVEL

Benign

0.14

Sift

Benign

0.22

T;T

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.96

D;D

Vest4

0.11

MVP

0.63

MPC

0.24

ClinPred

0.027

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.053

gMVP

0.13

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over