rs2248374

Variant names:

• chr5-96900192-A-G
• rs2248374
• NM_022350.5:c.1572+3A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022350.5(ERAP2):​c.1572+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,612,670 control chromosomes in the GnomAD database, including 218,571 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.54 (22361 hom., cov: 31)
  • Exomes 𝑓: 0.52 (196210 hom.)
• Consequence: ERAP2 NM_022350.5 splice_region, intron
• Scores: Splicing: ADA: 0.001093
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.823
• Publications: 106 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]

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]

ENSG00000247121 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP2	NM_022350.5	MANE Select	c.1572+3A>G		splice_region intron	N/A	NP_071745.1	Q6P179-1
	ERAP2	NM_001130140.3		c.1572+3A>G		splice_region intron	N/A	NP_001123612.1
	ERAP2	NM_001437802.1		c.1504-1314A>G		intron	N/A	NP_001424731.1	A0AAQ5BHS6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP2	ENST00000437043.8	TSL:1 MANE Select	c.1572+3A>G		splice_region intron	N/A	ENSP00000400376.3	Q6P179-1
	ERAP2	ENST00000379904.8	TSL:1	c.1437+3A>G		splice_region intron	N/A	ENSP00000369235.4	Q6P179-3
	ERAP2	ENST00000851668.1		c.1572+3A>G		splice_region intron	N/A	ENSP00000521727.1

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82288 AN: 151886 Hom.: 22359 Cov.: 31

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.539

GnomAD2 exomes AF: 0.548 AC: 137755 AN: 251208 AF XY: 0.547

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.621

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: 754668 AN: 1460666 Hom.: 196210 Cov.: 36 AF XY: 0.518 AC XY: 376595 AN XY: 726656

African (AFR) AF: 0.579 AC: 19369 AN: 33434

American (AMR) AF: 0.618 AC: 27620 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 15119 AN: 26108

East Asian (EAS) AF: 0.540 AC: 21429 AN: 39654

South Asian (SAS) AF: 0.587 AC: 50588 AN: 86228

European-Finnish (FIN) AF: 0.526 AC: 27952 AN: 53174

Middle Eastern (MID) AF: 0.611 AC: 3521 AN: 5760

European-Non Finnish (NFE) AF: 0.502 AC: 557738 AN: 1111272

Other (OTH) AF: 0.519 AC: 31332 AN: 60350

GnomAD4 genome AF: 0.542 AC: 82325 AN: 152004 Hom.: 22361 Cov.: 31 AF XY: 0.544 AC XY: 40407 AN XY: 74288

African (AFR) AF: 0.572 AC: 23691 AN: 41440

American (AMR) AF: 0.585 AC: 8938 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2025 AN: 3468

East Asian (EAS) AF: 0.556 AC: 2880 AN: 5176

South Asian (SAS) AF: 0.580 AC: 2797 AN: 4824

European-Finnish (FIN) AF: 0.531 AC: 5602 AN: 10554

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

European-Non Finnish (NFE) AF: 0.510 AC: 34652 AN: 67950

Other (OTH) AF: 0.534 AC: 1129 AN: 2114

Alfa AF: 0.532 Hom.: 11223

Bravo AF: 0.552

Asia WGS AF: 0.488 AC: 1700 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	-0.51
CADD	Benign	17
DANN	Benign	0.83
PhyloP100		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.51		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2248374; hg19: chr5-96235896; COSMIC: COSV65938706; COSMIC: COSV65938706;