2-127651226-C-A

Variant names:

• chr2-127651226-C-A
• rs1683742543
• NM_001161417.2:c.491C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001161417.2(GPR17):​c.491C>A​(p.Ala164Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GPR17 NM_001161417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR17	NM_001161417.2	c.491C>A	p.Ala164Asp	missense_variant	Exon 2 of 2	ENST00000486700.2	NP_001154889.1
LIMS2	NM_001161403.3	c.359+3198G>T		intron_variant	Intron 4 of 9	ENST00000355119.9	NP_001154875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR17	ENST00000486700.2	c.491C>A	p.Ala164Asp	missense_variant	Exon 2 of 2	1	NM_001161417.2	ENSP00000508383.1
LIMS2	ENST00000355119.9	c.359+3198G>T		intron_variant	Intron 4 of 9	1	NM_001161403.3	ENSP00000347240.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455598 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.575C>A (p.A192D) alteration is located in exon 4 (coding exon 2) of the GPR17 gene. This alteration results from a C to A substitution at nucleotide position 575, causing the alanine (A) at amino acid position 192 to be replaced by an aspartic acid (D). 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D;D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;.;.
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.1	M;M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D;D;D
Sift4G	Benign	0.18	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.84
MutPred		0.76		Loss of glycosylation at S197 (P = 0.1178);Loss of glycosylation at S197 (P = 0.1178);Loss of glycosylation at S197 (P = 0.1178);
MVP		0.92
MPC		1.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.87

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

Other links and lift over

dbSNP: rs1683742543; hg19: chr2-128408800;