5-96895352-T-G

Variant names:

• chr5-96895352-T-G
• rs34261036
• NM_022350.5:c.1232T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022350.5(ERAP2):​c.1232T>G​(p.Leu411Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00381 in 1,603,844 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (22 hom.)
• Consequence: ERAP2 NM_022350.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.77
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005635202).
• BP6: Variant 5-96895352-T-G is Benign according to our data. Variant chr5-96895352-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00386 (5601/1451536) while in subpopulation MID AF = 0.0211 (121/5746). AF 95% confidence interval is 0.018. There are 22 homozygotes in GnomAdExome4. There are 2869 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

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.1232T>G	p.Leu411Arg	missense	Exon 7 of 19	NP_071745.1	Q6P179-1
	ERAP2	NM_001130140.3		c.1232T>G	p.Leu411Arg	missense	Exon 7 of 19	NP_001123612.1
	ERAP2	NM_001437802.1		c.1232T>G	p.Leu411Arg	missense	Exon 7 of 18	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.1232T>G	p.Leu411Arg	missense	Exon 7 of 19	ENSP00000400376.3	Q6P179-1
	ERAP2	ENST00000379904.8	TSL:1	c.1097T>G	p.Leu366Arg	missense	Exon 6 of 18	ENSP00000369235.4	Q6P179-3
	ERAP2	ENST00000851668.1		c.1232T>G	p.Leu411Arg	missense	Exon 7 of 19	ENSP00000521727.1

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00406 AC: 1011 AN: 248918 AF XY: 0.00433

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00429

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00570

Gnomad OTH exome AF: 0.00592

GnomAD4 exome AF: 0.00386 AC: 5601 AN: 1451536 Hom.: 22 Cov.: 28 AF XY: 0.00397 AC XY: 2869 AN XY: 722640

African (AFR) AF: 0.000542 AC: 18 AN: 33212

American (AMR) AF: 0.00320 AC: 142 AN: 44306

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 120 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00401 AC: 343 AN: 85550

European-Finnish (FIN) AF: 0.00214 AC: 114 AN: 53372

Middle Eastern (MID) AF: 0.0211 AC: 121 AN: 5746

European-Non Finnish (NFE) AF: 0.00406 AC: 4477 AN: 1103766

Other (OTH) AF: 0.00443 AC: 266 AN: 60022

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00361 AC XY: 269 AN XY: 74480

African (AFR) AF: 0.000577 AC: 24 AN: 41574

American (AMR) AF: 0.00379 AC: 58 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4830

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00525 AC: 357 AN: 68018

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00481 Hom.: 18

Bravo AF: 0.00352

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00415 AC: 504

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00732

EpiControl AF: 0.00753

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.92	P
Vest4		0.80
MVP		0.37
MPC		0.38
ClinPred		0.027	T
GERP RS		4.7
Varity_R		0.95
gMVP		0.63
Mutation Taster		=79/21	polymorphism

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: rs34261036; hg19: chr5-96231056; COSMIC: COSV108222013; COSMIC: COSV108222013;