5-96901622-G-A

Variant names:

• chr5-96901622-G-A
• rs2287988
• NM_022350.5:c.1689G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_022350.5(ERAP2):​c.1689G>A​(p.Gln563Gln) 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 1,613,618 control chromosomes in the GnomAD database, including 218,582 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 (22344 hom., cov: 32)
  • Exomes 𝑓: 0.52 (196238 hom.)
• Consequence: ERAP2 NM_022350.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 48 publications found

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]

ENSG00000247121 (HGNC:):

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.575 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP2	NM_022350.5	MANE Select	c.1689G>A	p.Gln563Gln	synonymous	Exon 11 of 19	NP_071745.1
	ERAP2	NM_001130140.3		c.1689G>A	p.Gln563Gln	synonymous	Exon 11 of 19	NP_001123612.1
	ERAP2	NM_001437802.1		c.1620G>A	p.Gln540Gln	synonymous	Exon 10 of 18	NP_001424731.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP2	ENST00000437043.8	TSL:1 MANE Select	c.1689G>A	p.Gln563Gln	synonymous	Exon 11 of 19	ENSP00000400376.3
	ERAP2	ENST00000379904.8	TSL:1	c.1554G>A	p.Gln518Gln	synonymous	Exon 10 of 18	ENSP00000369235.4
	ERAP2	ENST00000510373.6	TSL:2	c.1689G>A	p.Gln563Gln	synonymous	Exon 11 of 19	ENSP00000421175.2

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82250 AN: 151892 Hom.: 22342 Cov.: 32

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.539

GnomAD2 exomes AF: 0.548 AC: 137649 AN: 251092 AF XY: 0.547

Gnomad AFR exome AF: 0.576

Gnomad AMR exome AF: 0.620

Gnomad ASJ exome AF: 0.576

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: 755105 AN: 1461608 Hom.: 196238 Cov.: 54 AF XY: 0.518 AC XY: 376823 AN XY: 727118

African (AFR) AF: 0.579 AC: 19387 AN: 33470

American (AMR) AF: 0.618 AC: 27620 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 15130 AN: 26130

East Asian (EAS) AF: 0.540 AC: 21443 AN: 39688

South Asian (SAS) AF: 0.587 AC: 50595 AN: 86242

European-Finnish (FIN) AF: 0.526 AC: 28071 AN: 53416

Middle Eastern (MID) AF: 0.611 AC: 3522 AN: 5764

European-Non Finnish (NFE) AF: 0.502 AC: 557982 AN: 1111820

Other (OTH) AF: 0.519 AC: 31355 AN: 60390

GnomAD4 genome AF: 0.541 AC: 82287 AN: 152010 Hom.: 22344 Cov.: 32 AF XY: 0.544 AC XY: 40382 AN XY: 74286

African (AFR) AF: 0.571 AC: 23685 AN: 41460

American (AMR) AF: 0.586 AC: 8940 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2026 AN: 3466

East Asian (EAS) AF: 0.555 AC: 2866 AN: 5164

South Asian (SAS) AF: 0.580 AC: 2791 AN: 4816

European-Finnish (FIN) AF: 0.530 AC: 5595 AN: 10548

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34646 AN: 67976

Other (OTH) AF: 0.535 AC: 1128 AN: 2110

Alfa AF: 0.531 Hom.: 31742

Bravo AF: 0.552

Asia WGS AF: 0.488 AC: 1699 AN: 3478

EpiCase AF: 0.517

EpiControl AF: 0.522

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.5
DANN	Benign	0.89
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2287988; hg19: chr5-96237326; COSMIC: COSV65939094; COSMIC: COSV65939094;