13-26759751-G-A

Variant names:

• chr13-26759751-G-A
• NM_005288.4:c.77C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005288.4(GPR12):​c.77C>T​(p.Ser26Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,460,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: GPR12 NM_005288.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

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]

ACMG classification

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=0.3849207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR12	NM_005288.4	c.77C>T	p.Ser26Leu	missense_variant	Exon 2 of 2	ENST00000405846.5	NP_005279.1
GPR12	XM_005266360.3	c.-88-313C>T		intron_variant	Intron 1 of 1		XP_005266417.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR12	ENST00000405846.5	c.77C>T	p.Ser26Leu	missense_variant	Exon 2 of 2	1	NM_005288.4	ENSP00000384932.3
GPR12	ENST00000381436.2	c.77C>T	p.Ser26Leu	missense_variant	Exon 1 of 1	6		ENSP00000370844.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460306 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 726102

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: 0.0000108

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.77C>T (p.S26L) alteration is located in exon 2 (coding exon 1) of the GPR12 gene. This alteration results from a C to T substitution at nucleotide position 77, causing the serine (S) at amino acid position 26 to be replaced by a leucine (L). 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	0.25
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	0.060
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.035	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.57	P;P
Vest4		0.47
MutPred		0.47		Loss of disorder (P = 0.0067);Loss of disorder (P = 0.0067);
MVP		0.59
MPC		0.71
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-27333888;