Genetic Variant ERAP2:p.Ala6Ser (chr5-96879701-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022350.5(ERAP2):c.16G>T(p.Ala6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ERAP2
NM_022350.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0130

Publications

0 publications found

Variant links:

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]

ERAP2 links:

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]

ERAP1 links:

ENSG00000247121 (HGNC:):

ENSG00000247121 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060270995).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERAP2	NM_022350.5	MANE Select	c.16G>T	p.Ala6Ser	missense	Exon 2 of 19	NP_071745.1	Q6P179-1
ERAP2	NM_001130140.3		c.16G>T	p.Ala6Ser	missense	Exon 2 of 19	NP_001123612.1
ERAP2	NM_001437802.1		c.16G>T	p.Ala6Ser	missense	Exon 2 of 18	NP_001424731.1	A0AAQ5BHS6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERAP2	ENST00000437043.8	TSL:1 MANE Select	c.16G>T	p.Ala6Ser	missense	Exon 2 of 19	ENSP00000400376.3	Q6P179-1
ERAP2	ENST00000379904.8	TSL:1	c.16G>T	p.Ala6Ser	missense	Exon 2 of 18	ENSP00000369235.4	Q6P179-3
ERAP2	ENST00000510309.1	TSL:1	c.16G>T	p.Ala6Ser	missense	Exon 1 of 4	ENSP00000425758.1	Q6P179-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.65

CADD

Benign

2.4

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.013

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.50

M_CAP

Benign

0.0045

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

PhyloP100

0.013

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.37

REVEL

Benign

0.013

Sift

Benign

0.13

Sift4G

Benign

0.12

Polyphen

0.16

Vest4

0.21

MutPred

0.34

Loss of stability (P = 0.0481)

MVP

0.12

MPC

0.045

ClinPred

0.14

GERP RS

1.5

PromoterAI

-0.0063

Neutral

(source)

Varity_R

0.034

gMVP

0.34

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over