5-96883857-C-T

Variant names:

• chr5-96883857-C-T
• rs3733905
• NM_022350.5:c.641C>T

Variant summary

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

The NM_022350.5(ERAP2):​c.641C>T​(p.Pro214Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0113 in 1,613,618 control chromosomes in the GnomAD database, including 708 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 0.0094 (44 hom., cov: 32)
  • Exomes 𝑓: 0.012 (664 hom.)
• Consequence: ERAP2 NM_022350.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.85
• Publications: 9 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 (MetaRNN=0.003774345).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.075 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.641C>T	p.Pro214Leu	missense	Exon 3 of 19	NP_071745.1
	ERAP2	NM_001130140.3		c.641C>T	p.Pro214Leu	missense	Exon 3 of 19	NP_001123612.1
	ERAP2	NM_001437802.1		c.641C>T	p.Pro214Leu	missense	Exon 3 of 18	NP_001424731.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERAP2	ENST00000437043.8	TSL:1 MANE Select	c.641C>T	p.Pro214Leu	missense	Exon 3 of 19	ENSP00000400376.3
	ERAP2	ENST00000379904.8	TSL:1	c.641C>T	p.Pro214Leu	missense	Exon 3 of 18	ENSP00000369235.4
	ERAP2	ENST00000510309.1	TSL:1	c.641C>T	p.Pro214Leu	missense	Exon 2 of 4	ENSP00000425758.1

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1432 AN: 152102 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.0655

Gnomad SAS AF: 0.0816

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0195 AC: 4884 AN: 250652 AF XY: 0.0232

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00308

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.0483

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.00442

Gnomad OTH exome AF: 0.0188

GnomAD4 exome AF: 0.0115 AC: 16811 AN: 1461398 Hom.: 664 Cov.: 30 AF XY: 0.0139 AC XY: 10071 AN XY: 726998

African (AFR) AF: 0.00129 AC: 43 AN: 33450

American (AMR) AF: 0.00371 AC: 166 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 902 AN: 26116

East Asian (EAS) AF: 0.0990 AC: 3924 AN: 39624

South Asian (SAS) AF: 0.0828 AC: 7138 AN: 86166

European-Finnish (FIN) AF: 0.0177 AC: 948 AN: 53410

Middle Eastern (MID) AF: 0.0330 AC: 190 AN: 5762

European-Non Finnish (NFE) AF: 0.00235 AC: 2618 AN: 1111798

Other (OTH) AF: 0.0146 AC: 882 AN: 60380

GnomAD4 genome AF: 0.00941 AC: 1433 AN: 152220 Hom.: 44 Cov.: 32 AF XY: 0.0118 AC XY: 879 AN XY: 74420

African (AFR) AF: 0.000770 AC: 32 AN: 41536

American (AMR) AF: 0.00471 AC: 72 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3468

East Asian (EAS) AF: 0.0655 AC: 339 AN: 5176

South Asian (SAS) AF: 0.0816 AC: 394 AN: 4826

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10590

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68014

Other (OTH) AF: 0.0114 AC: 24 AN: 2108

Alfa AF: 0.00728 Hom.: 34

Bravo AF: 0.00607

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.0205 AC: 2489

Asia WGS AF: 0.0660 AC: 229 AN: 3478

EpiCase AF: 0.00677

EpiControl AF: 0.00700

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	4.2	H
PhyloP100		5.8
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.51
MPC		0.33
ClinPred		0.11	T
GERP RS		3.3
Varity_R		0.94
gMVP		0.79
Mutation Taster		=91/9	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: rs3733905; hg19: chr5-96219561; COSMIC: COSV65939130; COSMIC: COSV65939130;