chr5-96903554-T-A

Variant names:

• chr5-96903554-T-A
• rs17408150
• NM_022350.5:c.2006T>A

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 30 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 -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.

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.2006T>A	p.Leu669Gln	missense	Exon 13 of 19	NP_071745.1
	ERAP2	NM_001130140.3		c.2006T>A	p.Leu669Gln	missense	Exon 13 of 19	NP_001123612.1
	ERAP2	NM_001437802.1		c.1937T>A	p.Leu646Gln	missense	Exon 12 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.2006T>A	p.Leu669Gln	missense	Exon 13 of 19	ENSP00000400376.3
	ERAP2	ENST00000379904.8	TSL:1	c.1871T>A	p.Leu624Gln	missense	Exon 12 of 18	ENSP00000369235.4
	ERAP2	ENST00000510373.6	TSL:2	c.2006T>A	p.Leu669Gln	missense	Exon 13 of 19	ENSP00000421175.2

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

GnomAD2 exomes AF: 0.0403 AC: 9445 AN: 234360 AF XY: 0.0421

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 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

African (AFR) AF: 0.0101 AC: 328 AN: 32626

American (AMR) AF: 0.0361 AC: 1430 AN: 39620

Ashkenazi Jewish (ASJ) AF: 0.0688 AC: 1730 AN: 25136

East Asian (EAS) AF: 0.000203 AC: 8 AN: 39422

South Asian (SAS) AF: 0.0315 AC: 2604 AN: 82576

European-Finnish (FIN) AF: 0.0211 AC: 1123 AN: 53148

Middle Eastern (MID) AF: 0.0968 AC: 551 AN: 5690

European-Non Finnish (NFE) AF: 0.0565 AC: 62476 AN: 1104826

Other (OTH) AF: 0.0526 AC: 3138 AN: 59650

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

African (AFR) AF: 0.00991 AC: 412 AN: 41576

American (AMR) AF: 0.0466 AC: 712 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0703 AC: 244 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4830

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10608

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0559 AC: 3800 AN: 68016

Other (OTH) AF: 0.0596 AC: 126 AN: 2114

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 v4.9

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
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.7
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.60
MPC		0.33
ClinPred		0.028	T
GERP RS		2.4
Varity_R		0.96
gMVP		0.69
Mutation Taster		=87/13	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: rs17408150; hg19: chr5-96239258; COSMIC: COSV107492899; COSMIC: COSV107492899;