Genetic Variant CPN2:p.Val536Leu (chr3-194341097-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001080513.4(CPN2):c.1606G>C(p.Val536Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CPN2
NM_001080513.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.528

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11704481).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPN2	NM_001080513.4 link	c.1606G>C	p.Val536Leu	missense_variant	Exon 2 of 2	ENST00000323830.4	NP_001073982.3	P22792
CPN2	NM_001291988.2 link	c.1606G>C	p.Val536Leu	missense_variant	Exon 2 of 2		NP_001278917.1	P22792
CPN2	XM_005269280.5 link	c.1606G>C	p.Val536Leu	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.1606G>C	p.Val536Leu	missense_variant	Exon 2 of 2	1	NM_001080513.4	ENSP00000319464.3		P22792
CPN2	ENST00000429275.1 link	c.1606G>C	p.Val536Leu	missense_variant	Exon 2 of 2	5		ENSP00000402232.1		P22792

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455764

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33368

American (AMR)

AF:

0.00

AC:

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39534

South Asian (SAS)

AF:

0.00

AC:

AN:

86028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52704

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5436

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108074

Other (OTH)

AF:

0.00

AC:

AN:

60044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.49

.;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.9

L;L

PhyloP100

0.53

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.27

N;N

REVEL

Benign

0.041

Sift

Uncertain

0.018

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.031

B;B

Vest4

0.077

MutPred

0.40

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);

MVP

0.56

MPC

0.23

ClinPred

0.13

GERP RS

2.8

Varity_R

0.056

gMVP

0.15

Mutation Taster

=94/6

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over