Genetic Variant NM_001080513.4:c.913G>A (chr3-194341790-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001080513.4(CPN2):c.913G>A(p.Ala305Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,613,682 control chromosomes in the GnomAD database, including 74,095 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 8607 hom., cov: 32)

Exomes 𝑓: 0.30 ( 65488 hom. )

Consequence

CPN2
NM_001080513.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.784

Publications

30 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.7690015E-4).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPN2	NM_001080513.4 link	c.913G>A	p.Ala305Thr	missense_variant	Exon 2 of 2	ENST00000323830.4	NP_001073982.3	P22792
CPN2	NM_001291988.2 link	c.913G>A	p.Ala305Thr	missense_variant	Exon 2 of 2		NP_001278917.1	P22792
CPN2	XM_005269280.5 link	c.913G>A	p.Ala305Thr	missense_variant	Exon 3 of 3		XP_005269337.1	P22792

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPN2	ENST00000323830.4 link	c.913G>A	p.Ala305Thr	missense_variant	Exon 2 of 2	1	NM_001080513.4	ENSP00000319464.3		P22792
CPN2	ENST00000429275.1 link	c.913G>A	p.Ala305Thr	missense_variant	Exon 2 of 2	5		ENSP00000402232.1		P22792

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

50173

AN:

151830

Hom.:

8603

Cov.:

show subpopulations

Gnomad AFR

AF:

0.420

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.273

Gnomad ASJ

AF:

0.341

Gnomad EAS

AF:

0.332

Gnomad SAS

AF:

0.410

Gnomad FIN

AF:

0.360

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.281

Gnomad OTH

AF:

0.304

GnomAD2 exomes

AF:

0.310

AC:

77937

AN:

251038

AF XY:

0.314

show subpopulations

Gnomad AFR exome

AF:

0.431

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.345

Gnomad EAS exome

AF:

0.339

Gnomad FIN exome

AF:

0.355

Gnomad NFE exome

AF:

0.280

Gnomad OTH exome

AF:

0.304

GnomAD4 exome

AF:

0.295

AC:

431658

AN:

1461734

Hom.:

65488

Cov.:

AF XY:

0.298

AC XY:

216801

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.429

AC:

14371

AN:

33480

American (AMR)

AF:

0.221

AC:

9884

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

9011

AN:

26136

East Asian (EAS)

AF:

0.356

AC:

14150

AN:

39696

South Asian (SAS)

AF:

0.407

AC:

35084

AN:

86254

European-Finnish (FIN)

AF:

0.355

AC:

18934

AN:

53368

Middle Eastern (MID)

AF:

0.327

AC:

1888

AN:

5768

European-Non Finnish (NFE)

AF:

0.279

AC:

309982

AN:

1111932

Other (OTH)

AF:

0.304

AC:

18354

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

19998

39996

59995

79993

99991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10558

21116

31674

42232

52790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.330

AC:

50206

AN:

151948

Hom.:

8607

Cov.:

AF XY:

0.334

AC XY:

24796

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.421

AC:

17413

AN:

41406

American (AMR)

AF:

0.272

AC:

4163

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.341

AC:

1184

AN:

3468

East Asian (EAS)

AF:

0.331

AC:

1710

AN:

5162

South Asian (SAS)

AF:

0.408

AC:

1962

AN:

4810

European-Finnish (FIN)

AF:

0.360

AC:

3809

AN:

10568

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.281

AC:

19092

AN:

67940

Other (OTH)

AF:

0.306

AC:

646

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1697

3395

5092

6790

8487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

512

1024

1536

2048

2560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.301

Hom.:

24231

Bravo

AF:

0.325

TwinsUK

AF:

0.286

AC:

1061

ALSPAC

AF:

0.288

AC:

1111

ESP6500AA

AF:

0.410

AC:

1807

ESP6500EA

AF:

0.283

AC:

2431

ExAC

AF:

0.314

AC:

38128

Asia WGS

AF:

0.384

AC:

1334

AN:

3478

EpiCase

AF:

0.285

EpiControl

AF:

0.278

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.37

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.40

.;T

MetaRNN

Benign

0.00068

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.38

N;N

PhyloP100

-0.78

PrimateAI

Benign

0.25

PROVEAN

Benign

0.22

N;N

REVEL

Benign

0.11

Sift

Benign

0.30

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.017

B;B

Vest4

0.0090

MPC

0.18

ClinPred

0.0095

GERP RS

-11

Varity_R

0.052

gMVP

0.30

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over