rs17408150

Positions:

• chr5-96903554-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022350.5(ERAP2):​c.2006T>A​(p.Leu669Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0496 in 1,594,986 control chromosomes in the GnomAD database, including 2,284 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.038 (189 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2095 hom.)
• Consequence: ERAP2 NM_022350.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.65

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]

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]

ERAP2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039714277).
• 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/exons	MANE	Protein	UniProt
ERAP2	NM_022350.5	c.2006T>A	p.Leu669Gln	missense_variant	13/19	ENST00000437043.8	NP_071745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERAP2	ENST00000437043.8	c.2006T>A	p.Leu669Gln	missense_variant	13/19	1	NM_022350.5	ENSP00000400376.3

Frequencies

GnomAD3 genomes AF: 0.0380 AC: 5786 AN: 152174 Hom.: 190 Cov.: 32

Gnomad AFR AF: 0.00994

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0466

Gnomad ASJ AF: 0.0703

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0558

Gnomad OTH AF: 0.0598

GnomAD3 exomes AF: 0.0403 AC: 9445 AN: 234360 Hom.: 265 AF XY: 0.0421 AC XY: 5325 AN XY: 126564

Gnomad AFR exome AF: 0.00834

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0735

Gnomad EAS exome AF: 0.000560

Gnomad SAS exome AF: 0.0318

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0561

Gnomad OTH exome AF: 0.0514

GnomAD4 exome AF: 0.0509 AC: 73388 AN: 1442694 Hom.: 2095 Cov.: 31 AF XY: 0.0509 AC XY: 36441 AN XY: 716500

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.0361

Gnomad4 ASJ exome AF: 0.0688

Gnomad4 EAS exome AF: 0.000203

Gnomad4 SAS exome AF: 0.0315

Gnomad4 FIN exome AF: 0.0211

Gnomad4 NFE exome AF: 0.0565

Gnomad4 OTH exome AF: 0.0526

GnomAD4 genome AF: 0.0380 AC: 5782 AN: 152292 Hom.: 189 Cov.: 32 AF XY: 0.0362 AC XY: 2694 AN XY: 74476

Gnomad4 AFR AF: 0.00991

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.0703

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.0559

Gnomad4 OTH AF: 0.0596

Alfa AF: 0.0535 Hom.: 197

Bravo AF: 0.0396

TwinsUK AF: 0.0577 AC: 214

ALSPAC AF: 0.0524 AC: 202

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0569 AC: 489

ExAC AF: 0.0397 AC: 4823

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.60
MPC		0.33
ClinPred		0.028	T
GERP RS		2.4
Varity_R		0.96
gMVP		0.69

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

LitVar

Other links and lift over

dbSNP: rs17408150; hg19: chr5-96239258;