5-96879813-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.72

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 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
ERAP2	NM_022350.5	c.128G>C	p.Ser43Thr	missense_variant	2/19	ENST00000437043.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERAP2	ENST00000437043.8	c.128G>C	p.Ser43Thr	missense_variant	2/19	1	NM_022350.5	P1
	ENST00000501338.5	n.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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The 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;