2-127651492-G-A

Variant summary

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

The NM_001161417.2(GPR17):​c.757G>A​(p.Val253Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,612,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

GPR17
NM_001161417.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.584
Variant links:
Genes affected
GPR17 (HGNC:4471): (G protein-coupled receptor 17) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in positive regulation of Rho protein signal transduction and positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway. Predicted to act upstream of or within negative regulation of inflammatory response to antigenic stimulus. Predicted to be located in plasma membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]
LIMS2 (HGNC:16084): (LIM zinc finger domain containing 2) This gene encodes a member of a small family of focal adhesion proteins which interacts with ILK (integrin-linked kinase), a protein which effects protein-protein interactions with the extraceullar matrix. The encoded protein has five LIM domains, each domain forming two zinc fingers, which permit interactions which regulate cell shape and migration. A pseudogene of this gene is located on chromosome 4. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

Genome browser will be placed here

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=0.021505654).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GPR17NM_001161417.2 linkc.757G>A p.Val253Ile missense_variant 2/2 ENST00000486700.2 NP_001154889.1 Q13304-2G4XH68
LIMS2NM_001161403.3 linkc.359+2932C>T intron_variant ENST00000355119.9 NP_001154875.1 Q7Z4I7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GPR17ENST00000486700.2 linkc.757G>A p.Val253Ile missense_variant 2/21 NM_001161417.2 ENSP00000508383.1 Q13304-2
LIMS2ENST00000355119.9 linkc.359+2932C>T intron_variant 1 NM_001161403.3 ENSP00000347240.4 Q7Z4I7-1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152252
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000132
AC:
33
AN:
250126
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
135484
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.000337
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000849
AC:
124
AN:
1460284
Hom.:
0
Cov.:
32
AF XY:
0.0000785
AC XY:
57
AN XY:
726536
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.000212
Gnomad4 NFE exome
AF:
0.0000782
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152370
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
AN XY:
74518
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.0000680
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.000124
AC:
15
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

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 GeneticsMay 01, 2022The c.841G>A (p.V281I) alteration is located in exon 4 (coding exon 2) of the GPR17 gene. This alteration results from a G to A substitution at nucleotide position 841, causing the valine (V) at amino acid position 281 to be replaced by an isoleucine (I). 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
0.071
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
8.8
DANN
Benign
0.90
DEOGEN2
Benign
0.037
T;T;T
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.73
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.74
T;.;.
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.022
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.30
N;N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
0.050
N;N;N
REVEL
Benign
0.044
Sift
Benign
1.0
T;T;T
Sift4G
Benign
0.49
T;T;T
Polyphen
0.018
B;B;B
Vest4
0.068
MVP
0.072
MPC
0.22
ClinPred
0.013
T
GERP RS
1.5
Varity_R
0.030
gMVP
0.16

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: rs200480389; hg19: chr2-128409066; API