2-218262986-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_170699.3(GPBAR1):​c.262G>A​(p.Val88Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

GPBAR1
NM_170699.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.368
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.035541296).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GPBAR1NM_170699.3 linkuse as main transcriptc.262G>A p.Val88Ile missense_variant 2/2 ENST00000519574.2 NP_733800.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GPBAR1ENST00000519574.2 linkuse as main transcriptc.262G>A p.Val88Ile missense_variant 2/21 NM_170699.3 ENSP00000430202 P1
GPBAR1ENST00000479077.5 linkuse as main transcriptc.262G>A p.Val88Ile missense_variant 2/22 ENSP00000430698 P1
GPBAR1ENST00000521462.1 linkuse as main transcriptc.262G>A p.Val88Ile missense_variant 2/22 ENSP00000428824 P1
GPBAR1ENST00000522678.5 linkuse as main transcriptc.262G>A p.Val88Ile missense_variant 2/22 ENSP00000430886 P1

Frequencies

GnomAD3 genomes
AF:
0.0000921
AC:
14
AN:
152058
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000361
AC:
9
AN:
249074
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135138
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000561
AC:
82
AN:
1461686
Hom.:
0
Cov.:
31
AF XY:
0.0000578
AC XY:
42
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000302
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152176
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74394
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000589
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.000155
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000495
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 10, 2022The c.262G>A (p.V88I) alteration is located in exon 2 (coding exon 1) of the GPBAR1 gene. This alteration results from a G to A substitution at nucleotide position 262, causing the valine (V) at amino acid position 88 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 20, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
16
DANN
Benign
0.96
DEOGEN2
Benign
0.050
T;T;T;T
Eigen
Benign
-0.59
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.59
.;.;.;T
M_CAP
Benign
0.0026
T
MetaRNN
Benign
0.036
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.46
N;N;N;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.010
N;N;N;N
REVEL
Benign
0.038
Sift
Benign
0.39
T;T;T;T
Sift4G
Benign
0.27
T;T;T;T
Polyphen
0.029
B;B;B;B
Vest4
0.074
MVP
0.15
MPC
0.039
ClinPred
0.010
T
GERP RS
2.4
Varity_R
0.047
gMVP
0.16

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: rs181236250; hg19: chr2-219127709; COSMIC: COSV50307873; COSMIC: COSV50307873; API