Genetic Variant NM_002062.5:c.502G>A (chr6-39066296-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.502G>A(p.Gly168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,594,086 control chromosomes in the GnomAD database, including 76,319 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 0.22 ( 4890 hom., cov: 33)

Exomes 𝑓: 0.30 ( 71429 hom. )

Consequence

GLP1R
NM_002062.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.107

Publications

126 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0050249994).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLP1R	NM_002062.5 link	c.502G>A	p.Gly168Ser	missense_variant	Exon 5 of 13	ENST00000373256.5	NP_002053.3	P43220A0A142FHB8
GLP1R	NR_136562.2 link	n.562G>A		non_coding_transcript_exon_variant	Exon 5 of 14
GLP1R	NR_136563.2 link	n.562G>A		non_coding_transcript_exon_variant	Exon 5 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLP1R	ENST00000373256.5 link	c.502G>A	p.Gly168Ser	missense_variant	Exon 5 of 13	1	NM_002062.5	ENSP00000362353.4		P43220

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33293

AN:

152040

Hom.:

4888

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0617

Gnomad AMI

AF:

0.155

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.0116

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.266

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.228

GnomAD2 exomes

AF:

0.230

AC:

57501

AN:

250114

AF XY:

0.235

show subpopulations

Gnomad AFR exome

AF:

0.0574

Gnomad AMR exome

AF:

0.137

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.0108

Gnomad FIN exome

AF:

0.276

Gnomad NFE exome

AF:

0.330

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.300

AC:

432743

AN:

1441928

Hom.:

71429

Cov.:

AF XY:

0.297

AC XY:

213090

AN XY:

718444

show subpopulations

African (AFR)

AF:

0.0522

AC:

1731

AN:

33186

American (AMR)

AF:

0.141

AC:

6314

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

6144

AN:

26012

East Asian (EAS)

AF:

0.00424

AC:

168

AN:

39638

South Asian (SAS)

AF:

0.149

AC:

12815

AN:

85898

European-Finnish (FIN)

AF:

0.276

AC:

14651

AN:

53064

Middle Eastern (MID)

AF:

0.239

AC:

1377

AN:

5752

European-Non Finnish (NFE)

AF:

0.342

AC:

373604

AN:

1093882

Other (OTH)

AF:

0.266

AC:

15939

AN:

59856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

12954

25908

38862

51816

64770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11534

23068

34602

46136

57670

<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:

0.219

AC:

33287

AN:

152158

Hom.:

4890

Cov.:

AF XY:

0.213

AC XY:

15817

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0615

AC:

2553

AN:

41524

American (AMR)

AF:

0.189

AC:

2885

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

847

AN:

3468

East Asian (EAS)

AF:

0.0116

AC:

AN:

5156

South Asian (SAS)

AF:

0.144

AC:

695

AN:

4822

European-Finnish (FIN)

AF:

0.266

AC:

2818

AN:

10596

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.335

AC:

22745

AN:

67982

Other (OTH)

AF:

0.225

AC:

477

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1271

2542

3814

5085

6356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

338

676

1014

1352

1690

<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:

0.285

Hom.:

25527

Bravo

AF:

0.204

TwinsUK

AF:

0.353

AC:

1310

ALSPAC

AF:

0.360

AC:

1386

ESP6500AA

AF:

0.0656

AC:

289

ESP6500EA

AF:

0.337

AC:

2896

ExAC

AF:

0.232

AC:

28145

Asia WGS

AF:

0.0700

AC:

246

AN:

3478

EpiCase

AF:

0.329

EpiControl

AF:

0.319

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.17

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.14

PhyloP100

0.11

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.67

REVEL

Benign

0.052

Sift

Benign

0.44

Sift4G

Benign

0.51

Polyphen

0.0010

Vest4

0.023

MPC

0.48

ClinPred

0.0010

GERP RS

-2.1

Varity_R

0.13

gMVP

0.35

Mutation Taster

=98/2

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