13-26759314-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005288.4(GPR12):​c.514G>A​(p.Gly172Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GPR12
NM_005288.4 missense

Scores

13
4
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.77
Variant links:
Genes affected
GPR12 (HGNC:4466): (G protein-coupled receptor 12) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in adenylate cyclase-activating G protein-coupled receptor signaling pathway and regulation of metabolic process. Predicted to act upstream of or within G protein-coupled receptor signaling pathway and cellular calcium ion homeostasis. Predicted to be integral component of plasma membrane. Predicted to be active in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GPR12NM_005288.4 linkc.514G>A p.Gly172Arg missense_variant Exon 2 of 2 ENST00000405846.5 NP_005279.1 P47775A8K2F5
GPR12XM_005266360.3 linkc.37G>A p.Gly13Arg missense_variant Exon 2 of 2 XP_005266417.1 B4DG25

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GPR12ENST00000405846.5 linkc.514G>A p.Gly172Arg missense_variant Exon 2 of 2 1 NM_005288.4 ENSP00000384932.3 P47775
GPR12ENST00000381436.2 linkc.514G>A p.Gly172Arg missense_variant Exon 1 of 1 6 ENSP00000370844.2 P47775

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250682
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135568
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461146
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726870
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
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
Nov 06, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.514G>A (p.G172R) alteration is located in exon 2 (coding exon 1) of the GPR12 gene. This alteration results from a G to A substitution at nucleotide position 514, causing the glycine (G) at amino acid position 172 to be replaced by an arginine (R). 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
1.0
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.53
D;D
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Benign
0.069
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Pathogenic
3.5
M;M
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-6.6
D;D
REVEL
Pathogenic
0.82
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
D;D
Vest4
0.98
MutPred
0.83
Gain of catalytic residue at L171 (P = 0);Gain of catalytic residue at L171 (P = 0);
MVP
0.86
MPC
2.0
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.95
gMVP
0.98

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: rs149004892; hg19: chr13-27333451; API