NM_022350.5:c.754C>G

Variant names:

• chr5-96886694-C-G
• NM_022350.5:c.754C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022350.5(ERAP2):​c.754C>G​(p.His252Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ERAP2 NM_022350.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24901325).

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.754C>G	p.His252Asp	missense	Exon 4 of 19	NP_071745.1	Q6P179-1
	ERAP2	NM_001130140.3		c.754C>G	p.His252Asp	missense	Exon 4 of 19	NP_001123612.1
	ERAP2	NM_001437802.1		c.754C>G	p.His252Asp	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.754C>G	p.His252Asp	missense	Exon 4 of 19	ENSP00000400376.3	Q6P179-1
	ERAP2	ENST00000510309.1	TSL:1	c.754C>G	p.His252Asp	missense	Exon 3 of 4	ENSP00000425758.1	Q6P179-4
	ERAP2	ENST00000379904.8	TSL:1	c.715-2491C>G		intron	N/A	ENSP00000369235.4	Q6P179-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399708 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 691806

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32626

American (AMR) AF: 0.00 AC: 0 AN: 43114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24724

East Asian (EAS) AF: 0.00 AC: 0 AN: 38552

South Asian (SAS) AF: 0.00 AC: 0 AN: 78392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5522

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1068510

Other (OTH) AF: 0.00 AC: 0 AN: 57090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	0.21
BayesDel_addAF	Benign	-0.0039	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.20
Sift	Benign	0.33	T
Sift4G	Benign	0.48	T
Polyphen		0.025	B
Vest4		0.70
MutPred		0.48		Loss of sheet (P = 0.0817)
MVP		0.19
MPC		0.34
ClinPred		0.90	D
GERP RS		4.1
Varity_R		0.35
gMVP		0.62
Mutation Taster		=73/27	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

hg19: chr5-96222398;