rs1042044

Positions:

• chr6-39073726-A-C
• chr6-39073726-A-G
• chr6-39073726-A-T

Variant summary

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

The NM_002062.5(GLP1R):​c.780A>C​(p.Leu260Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,613,212 control chromosomes in the GnomAD database, including 257,118 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.56 (24439 hom., cov: 31)
  • Exomes 𝑓: 0.56 (232679 hom.)
• Consequence: GLP1R NM_002062.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.656

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=9.427291E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLP1R	NM_002062.5	c.780A>C	p.Leu260Phe	missense_variant	7/13	ENST00000373256.5
GLP1R	NR_136562.2	n.840A>C		non_coding_transcript_exon_variant	7/14
GLP1R	NR_136563.2	n.840A>C		non_coding_transcript_exon_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLP1R	ENST00000373256.5	c.780A>C	p.Leu260Phe	missense_variant	7/13	1	NM_002062.5	P1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85637 AN: 151860 Hom.: 24400 Cov.: 31

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.557

GnomAD3 exomes AF: 0.565 AC: 141904 AN: 251338 Hom.: 40227 AF XY: 0.563 AC XY: 76532 AN XY: 135826

Gnomad AFR exome AF: 0.580

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.463

Gnomad EAS exome AF: 0.563

Gnomad SAS exome AF: 0.576

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.567

GnomAD4 exome AF: 0.563 AC: 823257 AN: 1461234 Hom.: 232679 Cov.: 43 AF XY: 0.563 AC XY: 409577 AN XY: 726954

Gnomad4 AFR exome AF: 0.575

Gnomad4 AMR exome AF: 0.611

Gnomad4 ASJ exome AF: 0.456

Gnomad4 EAS exome AF: 0.524

Gnomad4 SAS exome AF: 0.575

Gnomad4 FIN exome AF: 0.550

Gnomad4 NFE exome AF: 0.566

Gnomad4 OTH exome AF: 0.555

GnomAD4 genome AF: 0.564 AC: 85734 AN: 151978 Hom.: 24439 Cov.: 31 AF XY: 0.563 AC XY: 41848 AN XY: 74270

Gnomad4 AFR AF: 0.574

Gnomad4 AMR AF: 0.580

Gnomad4 ASJ AF: 0.477

Gnomad4 EAS AF: 0.547

Gnomad4 SAS AF: 0.588

Gnomad4 FIN AF: 0.538

Gnomad4 NFE AF: 0.563

Gnomad4 OTH AF: 0.562

Alfa AF: 0.555 Hom.: 59820

Bravo AF: 0.566

ESP6500AA AF: 0.580 AC: 2557

ESP6500EA AF: 0.559 AC: 4806

ExAC AF: 0.564 AC: 68424

EpiCase AF: 0.566

EpiControl AF: 0.551

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.035
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.080
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.000094	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.5	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	3.4	N
REVEL	Benign	0.059
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MutPred		0.56		Gain of glycosylation at S258 (P = 0.1894);
MPC		0.51
ClinPred		0.0022	T
GERP RS		3.9
Varity_R		0.063
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1042044; hg19: chr6-39041502;