dbSNP rs3765467: GLP1R:p.Arg131Gln (chr6-39065819-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002062.5(GLP1R):c.392G>A(p.Arg131Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,592,830 control chromosomes in the GnomAD database, including 1,569 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.016 ( 183 hom., cov: 33)

Exomes 𝑓: 0.015 ( 1386 hom. )

Consequence

GLP1R
NM_002062.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0720

Publications

61 publications found

Variant links:

Genes affected

GLP1R (HGNC:4324): (glucagon like peptide 1 receptor) This gene encodes a 7-transmembrane protein that functions as a receptor for glucagon-like peptide 1 (GLP-1) hormone, which stimulates glucose-induced insulin secretion. This receptor, which functions at the cell surface, becomes internalized in response to GLP-1 and GLP-1 analogs, and it plays an important role in the signaling cascades leading to insulin secretion. It also displays neuroprotective effects in animal models. Polymorphisms in this gene are associated with diabetes. The protein is an important drug target for the treatment of type 2 diabetes and stroke. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2016]

GLP1R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018741488).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLP1R	NM_002062.5 link	c.392G>A	p.Arg131Gln	missense_variant	Exon 4 of 13	ENST00000373256.5	NP_002053.3	P43220A0A142FHB8
GLP1R	NR_136562.2 link	n.452G>A		non_coding_transcript_exon_variant	Exon 4 of 14
GLP1R	NR_136563.2 link	n.452G>A		non_coding_transcript_exon_variant	Exon 4 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLP1R	ENST00000373256.5 link	c.392G>A	p.Arg131Gln	missense_variant	Exon 4 of 13	1	NM_002062.5	ENSP00000362353.4		P43220

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2443

AN:

152136

Hom.:

182

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.0505

Gnomad AMR

AF:

0.0317

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.217

Gnomad SAS

AF:

0.0915

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00276

Gnomad OTH

AF:

0.0192

GnomAD2 exomes

AF:

0.0361

AC:

8635

AN:

239524

AF XY:

0.0368

show subpopulations

Gnomad AFR exome

AF:

0.00250

Gnomad AMR exome

AF:

0.0455

Gnomad ASJ exome

AF:

0.00193

Gnomad EAS exome

AF:

0.234

Gnomad FIN exome

AF:

0.000355

Gnomad NFE exome

AF:

0.00272

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.0155

AC:

22265

AN:

1440576

Hom.:

1386

Cov.:

AF XY:

0.0173

AC XY:

12392

AN XY:

716940

show subpopulations

African (AFR)

AF:

0.00196

AC:

AN:

33112

American (AMR)

AF:

0.0467

AC:

2053

AN:

43962

Ashkenazi Jewish (ASJ)

AF:

0.00239

AC:

AN:

25930

East Asian (EAS)

AF:

0.206

AC:

8112

AN:

39404

South Asian (SAS)

AF:

0.0868

AC:

7339

AN:

84516

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.0151

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00294

AC:

3217

AN:

1095184

Other (OTH)

AF:

0.0221

AC:

1320

AN:

59656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1018

2036

3053

4071

5089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

348

696

1044

1392

1740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0161

AC:

2449

AN:

152254

Hom.:

183

Cov.:

AF XY:

0.0184

AC XY:

1371

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00269

AC:

112

AN:

41566

American (AMR)

AF:

0.0319

AC:

488

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.217

AC:

1118

AN:

5144

South Asian (SAS)

AF:

0.0901

AC:

434

AN:

4818

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00276

AC:

188

AN:

68010

Other (OTH)

AF:

0.0237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

109

218

328

437

546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00391

Hom.:

Bravo

AF:

0.0187

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.0348

AC:

4215

Asia WGS

AF:

0.111

AC:

383

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.17

PhyloP100

0.072

PrimateAI

Benign

0.30

PROVEAN

Benign

0.36

REVEL

Benign

0.085

Sift

Benign

0.57

Sift4G

Benign

0.49

Polyphen

0.0020

Vest4

0.043

MPC

0.53

ClinPred

0.023

GERP RS

0.78

Varity_R

0.094

gMVP

0.22

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over