2-218262758-C-T

Variant names:

• chr2-218262758-C-T
• rs747879212
• NM_170699.3:c.34C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_170699.3(GPBAR1):​c.34C>T​(p.Pro12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,607,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GPBAR1 NM_170699.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04275304).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170699.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPBAR1	NM_170699.3	MANE Select	c.34C>T	p.Pro12Ser	missense	Exon 2 of 2	NP_733800.1	Q8TDU6
	GPBAR1	NM_001077191.2		c.34C>T	p.Pro12Ser	missense	Exon 2 of 2	NP_001070659.1	Q8TDU6
	GPBAR1	NM_001077194.2		c.34C>T	p.Pro12Ser	missense	Exon 2 of 2	NP_001070662.1	Q8TDU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPBAR1	ENST00000519574.2	TSL:1 MANE Select	c.34C>T	p.Pro12Ser	missense	Exon 2 of 2	ENSP00000430202.1	Q8TDU6
	GPBAR1	ENST00000479077.5	TSL:2	c.34C>T	p.Pro12Ser	missense	Exon 2 of 2	ENSP00000430698.1	Q8TDU6
	GPBAR1	ENST00000521462.1	TSL:2	c.34C>T	p.Pro12Ser	missense	Exon 2 of 2	ENSP00000428824.1	Q8TDU6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455852 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723514

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108796

Other (OTH) AF: 0.00 AC: 0 AN: 60098

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.84
DANN	Benign	0.69
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.32
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.014
Sift	Benign	0.16	T
Sift4G	Benign	0.084	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.11		Gain of glycosylation at P12 (P = 0.0426)
MVP		0.040
MPC		0.044
ClinPred		0.22	T
GERP RS		-1.7
Varity_R		0.043
gMVP		0.43
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs747879212; hg19: chr2-219127481;