chr5-96879813-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022350.5(ERAP2):​c.128G>C​(p.Ser43Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ERAP2
NM_022350.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.72
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.048607707).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ERAP2NM_022350.5 linkuse as main transcriptc.128G>C p.Ser43Thr missense_variant 2/19 ENST00000437043.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ERAP2ENST00000437043.8 linkuse as main transcriptc.128G>C p.Ser43Thr missense_variant 2/191 NM_022350.5 P1Q6P179-1
ENST00000501338.5 linkuse as main transcriptn.1689-6435C>G intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 27, 2022The c.128G>C (p.S43T) alteration is located in exon 2 (coding exon 1) of the ERAP2 gene. This alteration results from a G to C substitution at nucleotide position 128, causing the serine (S) at amino acid position 43 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
0.0080
DANN
Benign
0.57
DEOGEN2
Benign
0.017
T;T;.;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.072
N
LIST_S2
Benign
0.36
T;T;T;T
M_CAP
Benign
0.0022
T
MetaRNN
Benign
0.049
T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N;.;N;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.60
N;N;N;N
REVEL
Benign
0.013
Sift
Benign
0.59
T;T;T;T
Sift4G
Benign
0.64
T;T;T;T
Polyphen
0.072
B;.;B;.
Vest4
0.12
MutPred
0.36
Gain of glycosylation at S43 (P = 0.0402);Gain of glycosylation at S43 (P = 0.0402);Gain of glycosylation at S43 (P = 0.0402);Gain of glycosylation at S43 (P = 0.0402);
MVP
0.095
MPC
0.045
ClinPred
0.046
T
GERP RS
-2.6
Varity_R
0.036
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-96215517; API