chr5-96895352-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]

(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	UniProt
ERAP2	NM_022350.5	c.1232T>G	p.Leu411Arg	missense_variant	7/19	ENST00000437043.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERAP2	ENST00000437043.8	c.1232T>G	p.Leu411Arg	missense_variant	7/19	1	NM_022350.5	P1
	ENST00000501338.5	n.1689-21974A>C		intron_variant, non_coding_transcript_variant		2

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;.;.
MutationTaster	Benign	0.91	D;D;D
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;