Genetic Variant ERAP2:p.Pro435Pro (chr5-96896438-T-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_022350.5(ERAP2):c.1305T>A(p.Pro435Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,612,288 control chromosomes in the GnomAD database, including 218,450 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 0.54 ( 22340 hom., cov: 31)

Exomes 𝑓: 0.52 ( 196110 hom. )

Consequence

ERAP2
NM_022350.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.98

Publications

40 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP7

Synonymous conserved (PhyloP=-1.98 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP2	NM_022350.5 link	c.1305T>A	p.Pro435Pro	synonymous_variant	Exon 8 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.1305T>A	p.Pro435Pro	synonymous_variant	Exon 8 of 19	1	NM_022350.5	ENSP00000400376.3		Q6P179-1

Frequencies

GnomAD3 genomes

AF:

0.542

AC:

82245

AN:

151856

Hom.:

22338

Cov.:

show subpopulations

Gnomad AFR

AF:

0.572

Gnomad AMI

AF:

0.486

Gnomad AMR

AF:

0.586

Gnomad ASJ

AF:

0.584

Gnomad EAS

AF:

0.556

Gnomad SAS

AF:

0.579

Gnomad FIN

AF:

0.531

Gnomad MID

AF:

0.561

Gnomad NFE

AF:

0.510

Gnomad OTH

AF:

0.538

GnomAD2 exomes

AF:

0.548

AC:

137286

AN:

250424

AF XY:

0.547

show subpopulations

Gnomad AFR exome

AF:

0.576

Gnomad AMR exome

AF:

0.620

Gnomad ASJ exome

AF:

0.575

Gnomad EAS exome

AF:

0.588

Gnomad FIN exome

AF:

0.527

Gnomad NFE exome

AF:

0.511

Gnomad OTH exome

AF:

0.538

GnomAD4 exome

AF:

0.517

AC:

754400

AN:

1460314

Hom.:

196110

Cov.:

AF XY:

0.518

AC XY:

376450

AN XY:

726470

show subpopulations

African (AFR)

AF:

0.579

AC:

19343

AN:

33400

American (AMR)

AF:

0.618

AC:

27546

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

15114

AN:

26100

East Asian (EAS)

AF:

0.540

AC:

21404

AN:

39628

South Asian (SAS)

AF:

0.587

AC:

50538

AN:

86134

European-Finnish (FIN)

AF:

0.525

AC:

28050

AN:

53380

Middle Eastern (MID)

AF:

0.611

AC:

3521

AN:

5762

European-Non Finnish (NFE)

AF:

0.502

AC:

557562

AN:

1111002

Other (OTH)

AF:

0.519

AC:

31322

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

18184

36368

54552

72736

90920

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16358

32716

49074

65432

81790

<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:

0.541

AC:

82282

AN:

151974

Hom.:

22340

Cov.:

AF XY:

0.544

AC XY:

40378

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.571

AC:

23667

AN:

41452

American (AMR)

AF:

0.586

AC:

8940

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.584

AC:

2023

AN:

3464

East Asian (EAS)

AF:

0.556

AC:

2883

AN:

5182

South Asian (SAS)

AF:

0.580

AC:

2794

AN:

4816

European-Finnish (FIN)

AF:

0.531

AC:

5595

AN:

10544

Middle Eastern (MID)

AF:

0.575

AC:

168

AN:

292

European-Non Finnish (NFE)

AF:

0.510

AC:

34643

AN:

67938

Other (OTH)

AF:

0.534

AC:

1126

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1986

3972

5959

7945

9931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

724

1448

2172

2896

3620

<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:

0.525

Hom.:

6844

Bravo

AF:

0.552

Asia WGS

AF:

0.488

AC:

1698

AN:

3478

EpiCase

AF:

0.517

EpiControl

AF:

0.522

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.1

(source)

DANN

Benign

0.85

PhyloP100

-2.0

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