5-96895352-T-G

Position:

• chr5-96895352-T-G

Variant summary

Our verdict is Benign. Variant got -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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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:2
• Conservation: PhyloP100: 4.77

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]

ERAP2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 198587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-96895352-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 2869 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERAP2	NM_022350.5	c.1232T>G	p.Leu411Arg	missense_variant	7/19	ENST00000437043.8	NP_071745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERAP2	ENST00000437043.8	c.1232T>G	p.Leu411Arg	missense_variant	7/19	1	NM_022350.5	ENSP00000400376.3

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

GnomAD3 exomes AF: 0.00406 AC: 1011 AN: 248918 Hom.: 5 AF XY: 0.00433 AC XY: 583 AN XY: 134500

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 SAS exome AF: 0.00461

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

Gnomad4 AFR exome AF: 0.000542

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00461

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00401

Gnomad4 FIN exome AF: 0.00214

Gnomad4 NFE exome AF: 0.00406

Gnomad4 OTH exome AF: 0.00443

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

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00531 Hom.: 3

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

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 15, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

ERAP2: BS2 -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.92	P;.;D
Vest4		0.80
MVP		0.37
MPC		0.38
ClinPred		0.027	T
GERP RS		4.7
Varity_R		0.95
gMVP		0.63

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: rs34261036; hg19: chr5-96231056;