2-218262963-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_170699.3(GPBAR1):c.239G>A(p.Arg80Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: GPBAR1 NM_170699.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.930

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02738148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPBAR1	NM_170699.3	c.239G>A	p.Arg80Gln	missense_variant	2/2	ENST00000519574.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPBAR1	ENST00000519574.2	c.239G>A	p.Arg80Gln	missense_variant	2/2	1	NM_170699.3	P1
GPBAR1	ENST00000479077.5	c.239G>A	p.Arg80Gln	missense_variant	2/2	2		P1
GPBAR1	ENST00000521462.1	c.239G>A	p.Arg80Gln	missense_variant	2/2	2		P1
GPBAR1	ENST00000522678.5	c.239G>A	p.Arg80Gln	missense_variant	2/2	2		P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000100 AC: 25 AN: 248940 Hom.: 0 AF XY: 0.0000888 AC XY: 12 AN XY: 135064

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461668 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 727114

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74304

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.000459 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 08, 2017

- -

GPBAR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2023

The GPBAR1 c.239G>A variant is predicted to result in the amino acid substitution p.Arg80Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219127686-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.041	T;T;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.18	N
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.027	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.22	N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.068	B;B;B;B
Vest4		0.13
MVP		0.19
MPC		0.048
ClinPred		0.014	T
GERP RS		2.1
Varity_R		0.057
gMVP		0.22

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: rs201747442; hg19: chr2-219127686;