5-96895296-G-T

Variant names:

Variant summary

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

The NM_022350.5(ERAP2):c.1176G>T(p.Lys392Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,610,802 control chromosomes in the GnomAD database, including 218,341 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.54 ( 22335 hom., cov: 32)

Exomes 𝑓: 0.52 ( 196006 hom. )

Consequence

ERAP2
NM_022350.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.181

Publications

132 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:

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:

ENSG00000247121 (HGNC:):

ENSG00000247121 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=1.7660846E-5).

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022350.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERAP2	NM_022350.5	MANE Select	c.1176G>T	p.Lys392Asn	missense	Exon 7 of 19	NP_071745.1	Q6P179-1
ERAP2	NM_001130140.3		c.1176G>T	p.Lys392Asn	missense	Exon 7 of 19	NP_001123612.1
ERAP2	NM_001437802.1		c.1176G>T	p.Lys392Asn	missense	Exon 7 of 18	NP_001424731.1	A0AAQ5BHS6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERAP2	ENST00000437043.8	TSL:1 MANE Select	c.1176G>T	p.Lys392Asn	missense	Exon 7 of 19	ENSP00000400376.3	Q6P179-1
ERAP2	ENST00000379904.8	TSL:1	c.1041G>T	p.Lys347Asn	missense	Exon 6 of 18	ENSP00000369235.4	Q6P179-3
ERAP2	ENST00000851668.1		c.1176G>T	p.Lys392Asn	missense	Exon 7 of 19	ENSP00000521727.1

Frequencies

GnomAD3 genomes

AF:

0.542

AC:

82233

AN:

151838

Hom.:

22333

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:

0.555

Gnomad SAS

AF:

0.578

Gnomad FIN

AF:

0.530

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.510

Gnomad OTH

AF:

0.540

GnomAD2 exomes

AF:

0.548

AC:

136970

AN:

249984

AF XY:

0.547

show subpopulations

Gnomad AFR exome

AF:

0.576

Gnomad AMR exome

AF:

0.619

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:

0.537

GnomAD4 exome

AF:

0.517

AC:

753585

AN:

1458846

Hom.:

196006

Cov.:

AF XY:

0.518

AC XY:

376065

AN XY:

725772

show subpopulations

African (AFR)

AF:

0.579

AC:

19319

AN:

33350

American (AMR)

AF:

0.618

AC:

27446

AN:

44446

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

15104

AN:

26086

East Asian (EAS)

AF:

0.540

AC:

21373

AN:

39552

South Asian (SAS)

AF:

0.586

AC:

50315

AN:

85824

European-Finnish (FIN)

AF:

0.526

AC:

28054

AN:

53382

Middle Eastern (MID)

AF:

0.611

AC:

3519

AN:

5760

European-Non Finnish (NFE)

AF:

0.502

AC:

557173

AN:

1110176

Other (OTH)

AF:

0.519

AC:

31282

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

17682

35364

53045

70727

88409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16340

32680

49020

65360

81700

<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:

82270

AN:

151956

Hom.:

22335

Cov.:

AF XY:

0.544

AC XY:

40359

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.571

AC:

23686

AN:

41460

American (AMR)

AF:

0.586

AC:

8933

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.584

AC:

2026

AN:

3472

East Asian (EAS)

AF:

0.556

AC:

2871

AN:

5168

South Asian (SAS)

AF:

0.579

AC:

2794

AN:

4822

European-Finnish (FIN)

AF:

0.530

AC:

5591

AN:

10548

Middle Eastern (MID)

AF:

0.568

AC:

166

AN:

292

European-Non Finnish (NFE)

AF:

0.510

AC:

34633

AN:

67924

Other (OTH)

AF:

0.535

AC:

1127

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1917

3834

5752

7669

9586

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:

0.529

Hom.:

78973

Bravo

AF:

0.552

TwinsUK

AF:

0.498

AC:

1846

ALSPAC

AF:

0.495

AC:

1909

ESP6500AA

AF:

0.580

AC:

2555

ESP6500EA

AF:

0.521

AC:

4481

ExAC

AF:

0.547

AC:

66470

Asia WGS

AF:

0.487

AC:

1695

AN:

3476

EpiCase

AF:

0.517

EpiControl

AF:

0.522

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.039

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.035

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.67

MetaRNN

Benign

0.000018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.4

PhyloP100

0.18

PrimateAI

Benign

0.40

PROVEAN

Benign

5.2

REVEL

Benign

0.067

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.10

MutPred

0.30

Gain of catalytic residue at K392 (P = 0.0252)

MPC

0.053

ClinPred

0.00072

GERP RS

0.68

Varity_R

0.21

gMVP

0.33

Mutation Taster

=89/11

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over