2-127651255-C-A

Position:

• chr2-127651255-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001161417.2(GPR17):​c.520C>A​(p.Gln174Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 0.868

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]

GPR17 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06875515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR17	NM_001161417.2	c.520C>A	p.Gln174Lys	missense_variant	2/2	ENST00000486700.2	NP_001154889.1
LIMS2	NM_001161403.3	c.359+3169G>T		intron_variant		ENST00000355119.9	NP_001154875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR17	ENST00000486700.2	c.520C>A	p.Gln174Lys	missense_variant	2/2	1	NM_001161417.2	ENSP00000508383.1
LIMS2	ENST00000355119.9	c.359+3169G>T		intron_variant		1	NM_001161403.3	ENSP00000347240.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453866 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 723374

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2024

The c.604C>A (p.Q202K) 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 604, causing the glutamine (Q) at amino acid position 202 to be replaced by a lysine (K). 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	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.043	T;T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.63	T;.;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.53	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.31	N;N;N
REVEL	Benign	0.050
Sift	Benign	0.51	T;T;T
Sift4G	Benign	0.81	T;T;T
Polyphen		0.080	B;B;B
Vest4		0.18
MutPred		0.48		Gain of methylation at Q202 (P = 0.0043);Gain of methylation at Q202 (P = 0.0043);Gain of methylation at Q202 (P = 0.0043);
MVP		0.030
MPC		0.37
ClinPred		0.18	T
GERP RS		3.5
Varity_R		0.19
gMVP		0.47

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: rs1683746875; hg19: chr2-128408829;