Genetic Variant NM_022350.5:c.2067T>C (chr5-96909015-T-C) – 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.2067T>C(p.His689His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0494 in 1,614,024 control chromosomes in the GnomAD database, including 2,305 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 0.038 ( 189 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2116 hom. )

Consequence

ERAP2
NM_022350.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.126

Publications

10 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=-0.73).

BP7

Synonymous conserved (PhyloP=-0.126 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERAP2	NM_022350.5 link	c.2067T>C	p.His689His	synonymous_variant	Exon 14 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.2067T>C	p.His689His	synonymous_variant	Exon 14 of 19	1	NM_022350.5	ENSP00000400376.3		Q6P179-1

Frequencies

GnomAD3 genomes

AF:

0.0379

AC:

5772

AN:

152144

Hom.:

190

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00992

Gnomad AMI

AF:

0.117

Gnomad AMR

AF:

0.0460

Gnomad ASJ

AF:

0.0698

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0285

Gnomad FIN

AF:

0.0193

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0559

Gnomad OTH

AF:

0.0589

GnomAD2 exomes

AF:

0.0399

AC:

10042

AN:

251448

AF XY:

0.0415

show subpopulations

Gnomad AFR exome

AF:

0.00837

Gnomad AMR exome

AF:

0.0331

Gnomad ASJ exome

AF:

0.0718

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0194

Gnomad NFE exome

AF:

0.0558

Gnomad OTH exome

AF:

0.0508

GnomAD4 exome

AF:

0.0506

AC:

74020

AN:

1461762

Hom.:

2116

Cov.:

AF XY:

0.0506

AC XY:

36783

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.0102

AC:

343

AN:

33480

American (AMR)

AF:

0.0352

AC:

1573

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0687

AC:

1795

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39680

South Asian (SAS)

AF:

0.0314

AC:

2706

AN:

86258

European-Finnish (FIN)

AF:

0.0212

AC:

1132

AN:

53418

Middle Eastern (MID)

AF:

0.0962

AC:

555

AN:

5768

European-Non Finnish (NFE)

AF:

0.0564

AC:

62735

AN:

1111914

Other (OTH)

AF:

0.0526

AC:

3178

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

3534

7068

10603

14137

17671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2284

4568

6852

9136

11420

<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:

0.0379

AC:

5768

AN:

152262

Hom.:

189

Cov.:

AF XY:

0.0361

AC XY:

2685

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00989

AC:

411

AN:

41552

American (AMR)

AF:

0.0460

AC:

703

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0698

AC:

242

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0286

AC:

138

AN:

4832

European-Finnish (FIN)

AF:

0.0193

AC:

205

AN:

10600

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0559

AC:

3802

AN:

68010

Other (OTH)

AF:

0.0588

AC:

124

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

292

584

875

1167

1459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0542

Hom.:

365

Bravo

AF:

0.0396

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0647

EpiControl

AF:

0.0676

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.8

(source)

DANN

Benign

0.62

PhyloP100

-0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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