chr5-96886737-A-G

Variant names:

• chr5-96886737-A-G
• rs979604418
• NM_022350.5:c.797A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022350.5(ERAP2):​c.797A>G​(p.Tyr266Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 1,539,082 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ERAP2 NM_022350.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0790
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.797A>G	p.Tyr266Cys	missense	Exon 4 of 19	NP_071745.1	Q6P179-1
	ERAP2	NM_001130140.3		c.797A>G	p.Tyr266Cys	missense	Exon 4 of 19	NP_001123612.1
	ERAP2	NM_001437802.1		c.797A>G	p.Tyr266Cys	missense	Exon 4 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.797A>G	p.Tyr266Cys	missense	Exon 4 of 19	ENSP00000400376.3	Q6P179-1
	ERAP2	ENST00000510309.1	TSL:1	c.797A>G	p.Tyr266Cys	missense	Exon 3 of 4	ENSP00000425758.1	Q6P179-4
	ERAP2	ENST00000379904.8	TSL:1	c.715-2448A>G		intron	N/A	ENSP00000369235.4	Q6P179-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1386866 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 685380

African (AFR) AF: 0.0000308 AC: 1 AN: 32466

American (AMR) AF: 0.00 AC: 0 AN: 42704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24416

East Asian (EAS) AF: 0.00 AC: 0 AN: 38264

South Asian (SAS) AF: 0.00 AC: 0 AN: 75886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5474

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060904

Other (OTH) AF: 0.00 AC: 0 AN: 56424

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74368

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0067	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.058
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0097	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.079
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.65		Gain of helix (P = 0.1736)
MVP		0.26
MPC		0.34
ClinPred		0.96	D
GERP RS		-1.4
Varity_R		0.83
gMVP		0.70
Mutation Taster		=78/22	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: rs979604418; hg19: chr5-96222441;