chr5-96883861-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022350.5(ERAP2):ā€‹c.645G>Cā€‹(p.Leu215Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

ERAP2
NM_022350.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.387
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31047705).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ERAP2NM_022350.5 linkuse as main transcriptc.645G>C p.Leu215Phe missense_variant 3/19 ENST00000437043.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ERAP2ENST00000437043.8 linkuse as main transcriptc.645G>C p.Leu215Phe missense_variant 3/191 NM_022350.5 P1Q6P179-1
ENST00000501338.5 linkuse as main transcriptn.1689-10483C>G intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1461576
Hom.:
0
Cov.:
30
AF XY:
0.0000261
AC XY:
19
AN XY:
727096
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

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 GeneticsSep 20, 2023The c.645G>C (p.L215F) alteration is located in exon 3 (coding exon 2) of the ERAP2 gene. This alteration results from a G to C substitution at nucleotide position 645, causing the leucine (L) at amino acid position 215 to be replaced by a phenylalanine (F). 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
0.10
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
13
DANN
Uncertain
1.0
DEOGEN2
Benign
0.013
T;T;.;.
Eigen
Benign
-0.38
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.83
T;T;D;T
M_CAP
Benign
0.0048
T
MetaRNN
Benign
0.31
T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.18
N;.;N;N
MutationTaster
Benign
0.99
N;N;N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.1
N;N;N;N
REVEL
Benign
0.059
Sift
Uncertain
0.0060
D;D;D;D
Sift4G
Uncertain
0.010
D;D;D;T
Polyphen
0.29
B;.;B;.
Vest4
0.18
MutPred
0.69
Loss of catalytic residue at L215 (P = 0.0977);Loss of catalytic residue at L215 (P = 0.0977);Loss of catalytic residue at L215 (P = 0.0977);Loss of catalytic residue at L215 (P = 0.0977);
MVP
0.14
MPC
0.22
ClinPred
0.60
D
GERP RS
2.2
Varity_R
0.24
gMVP
0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs757064973; hg19: chr5-96219565; API