rs17408150

Positions:

• chr5-96903554-T-A

Variant summary

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

The ENST00000437043.8(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 ENST00000437043.8 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]

(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	P1
	ENST00000501338.5	n.1689-30176A>T		intron_variant, non_coding_transcript_variant		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

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;.;.
MutationTaster	Benign	0.99	D;D;D
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;