Genetic Variant ERAP2:p.Pro214Leu (chr5-96883857-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_022350.5(ERAP2):c.641C>T(p.Pro214Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0113 in 1,613,618 control chromosomes in the GnomAD database, including 708 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 0.0094 ( 44 hom., cov: 32)

Exomes 𝑓: 0.012 ( 664 hom. )

Consequence

ERAP2
NM_022350.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.85

Publications

9 publications found

Variant links:

Genes affected

ERAP2 (HGNC:29499): (endoplasmic reticulum aminopeptidase 2) This gene encodes a zinc metalloaminopeptidase of the M1 protease family that resides in the endoplasmic reticulum and functions in N-terminal trimming antigenic epitopes for presentation by major histocompatibility complex (MHC) class I molecules. Certain mutations in this gene are associated with the inflammatory arthritis syndrome ankylosing spondylitis and pre-eclampsia. This gene is located adjacent to a closely related aminopeptidase gene on chromosome 5. [provided by RefSeq, Jul 2016]

ERAP2 links:

ENSG00000247121 (HGNC:):

ENSG00000247121 links:

ERAP1 (HGNC:18173): (endoplasmic reticulum aminopeptidase 1) The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

ERAP1 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=0.003774345).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP2	NM_022350.5 link	c.641C>T	p.Pro214Leu	missense_variant	Exon 3 of 19	ENST00000437043.8	NP_071745.1	Q6P179-1B2R769

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERAP2	ENST00000437043.8 link	c.641C>T	p.Pro214Leu	missense_variant	Exon 3 of 19	1	NM_022350.5	ENSP00000400376.3		Q6P179-1

Frequencies

GnomAD3 genomes

AF:

0.00941

AC:

1432

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.0655

Gnomad SAS

AF:

0.0816

Gnomad FIN

AF:

0.0199

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00341

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0195

AC:

4884

AN:

250652

AF XY:

0.0232

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00308

Gnomad ASJ exome

AF:

0.0354

Gnomad EAS exome

AF:

0.0483

Gnomad FIN exome

AF:

0.0173

Gnomad NFE exome

AF:

0.00442

Gnomad OTH exome

AF:

0.0188

GnomAD4 exome

AF:

0.0115

AC:

16811

AN:

1461398

Hom.:

664

Cov.:

AF XY:

0.0139

AC XY:

10071

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00129

AC:

AN:

33450

American (AMR)

AF:

0.00371

AC:

166

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0345

AC:

902

AN:

26116

East Asian (EAS)

AF:

0.0990

AC:

3924

AN:

39624

South Asian (SAS)

AF:

0.0828

AC:

7138

AN:

86166

European-Finnish (FIN)

AF:

0.0177

AC:

948

AN:

53410

Middle Eastern (MID)

AF:

0.0330

AC:

190

AN:

5762

European-Non Finnish (NFE)

AF:

0.00235

AC:

2618

AN:

1111798

Other (OTH)

AF:

0.0146

AC:

882

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

722

1444

2167

2889

3611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<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:

0.00941

AC:

1433

AN:

152220

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

879

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41536

American (AMR)

AF:

0.00471

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

121

AN:

3468

East Asian (EAS)

AF:

0.0655

AC:

339

AN:

5176

South Asian (SAS)

AF:

0.0816

AC:

394

AN:

4826

European-Finnish (FIN)

AF:

0.0199

AC:

211

AN:

10590

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00341

AC:

232

AN:

68014

Other (OTH)

AF:

0.0114

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

148

221

295

369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00728

Hom.:

Bravo

AF:

0.00607

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.0205

AC:

2489

Asia WGS

AF:

0.0660

AC:

229

AN:

3478

EpiCase

AF:

0.00677

EpiControl

AF:

0.00700

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D;D;D

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Pathogenic

4.2

H;.;H;H

PhyloP100

5.8

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-8.9

D;D;D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.51

MPC

0.33

ClinPred

0.11

GERP RS

3.3

Varity_R

0.94

gMVP

0.79

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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