2-218262836-G-C

Position:

• chr2-218262836-G-C

Variant summary

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

The NM_170699.3(GPBAR1):​c.112G>C​(p.Gly38Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPBAR1 NM_170699.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.11

Genes affected

GPBAR1 (HGNC:19680): (G protein-coupled bile acid receptor 1) This gene encodes a member of the G protein-coupled receptor (GPCR) superfamily. This enzyme functions as a cell surface receptor for bile acids. Treatment of cells expressing this GPCR with bile acids induces the production of intracellular cAMP, activation of a MAP kinase signaling pathway, and internalization of the receptor. The receptor is implicated in the suppression of macrophage functions and regulation of energy homeostasis by bile acids. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

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, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPBAR1	NM_170699.3	c.112G>C	p.Gly38Arg	missense_variant	2/2	ENST00000519574.2	NP_733800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPBAR1	ENST00000519574.2	c.112G>C	p.Gly38Arg	missense_variant	2/2	1	NM_170699.3	ENSP00000430202	P1
GPBAR1	ENST00000479077.5	c.112G>C	p.Gly38Arg	missense_variant	2/2	2		ENSP00000430698	P1
GPBAR1	ENST00000521462.1	c.112G>C	p.Gly38Arg	missense_variant	2/2	2		ENSP00000428824	P1
GPBAR1	ENST00000522678.5	c.112G>C	p.Gly38Arg	missense_variant	2/2	2		ENSP00000430886	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 31, 2024

The c.112G>C (p.G38R) alteration is located in exon 2 (coding exon 1) of the GPBAR1 gene. This alteration results from a G to C substitution at nucleotide position 112, causing the glycine (G) at amino acid position 38 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	0.74
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;T;T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	.;.;.;T
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.9	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.89
MutPred		0.49		Gain of MoRF binding (P = 0.0561);Gain of MoRF binding (P = 0.0561);Gain of MoRF binding (P = 0.0561);Gain of MoRF binding (P = 0.0561);
MVP		0.59
MPC		0.33
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.84
gMVP		0.79

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: rs1341204755; hg19: chr2-219127559;