chr6-39065819-G-A

Position:

• chr6-39065819-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (183 hom., cov: 33)
  • Exomes 𝑓: 0.015 (1386 hom.)
• Consequence: GLP1R NM_002062.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0720

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
GLP1R	NM_002062.5	c.392G>A	p.Arg131Gln	missense_variant	4/13	ENST00000373256.5	NP_002053.3
GLP1R	NR_136562.2	n.452G>A		non_coding_transcript_exon_variant	4/14
GLP1R	NR_136563.2	n.452G>A		non_coding_transcript_exon_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLP1R	ENST00000373256.5	c.392G>A	p.Arg131Gln	missense_variant	4/13	1	NM_002062.5	ENSP00000362353	P1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2443 AN: 152136 Hom.: 182 Cov.: 33

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

GnomAD3 exomes AF: 0.0361 AC: 8635 AN: 239524 Hom.: 648 AF XY: 0.0368 AC XY: 4762 AN XY: 129430

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 SAS exome AF: 0.0863

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.: 27 AF XY: 0.0173 AC XY: 12392 AN XY: 716940

Gnomad4 AFR exome AF: 0.00196

Gnomad4 AMR exome AF: 0.0467

Gnomad4 ASJ exome AF: 0.00239

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.0868

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.00294

Gnomad4 OTH exome AF: 0.0221

GnomAD4 genome AF: 0.0161 AC: 2449 AN: 152254 Hom.: 183 Cov.: 33 AF XY: 0.0184 AC XY: 1371 AN XY: 74430

Gnomad4 AFR AF: 0.00269

Gnomad4 AMR AF: 0.0319

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.217

Gnomad4 SAS AF: 0.0901

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.00344 Hom.: 8

Bravo AF: 0.0187

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00268 AC: 23

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	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.17	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.085
Sift	Benign	0.57	T
Sift4G	Benign	0.49	T
Polyphen		0.0020	B
Vest4		0.043
MPC		0.53
ClinPred		0.023	T
GERP RS		0.78
Varity_R		0.094
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: rs3765467; hg19: chr6-39033595; COSMIC: COSV64714195;