chr6-39073726-A-C

Variant names:

• chr6-39073726-A-C
• rs1042044
• NM_002062.5:c.780A>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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 0.56 (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
• Publications: 74 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GLP1R	NM_002062.5	c.780A>C	p.Leu260Phe	missense_variant	Exon 7 of 13	ENST00000373256.5	NP_002053.3
GLP1R	NR_136562.2	n.840A>C		non_coding_transcript_exon_variant	Exon 7 of 14
GLP1R	NR_136563.2	n.840A>C		non_coding_transcript_exon_variant	Exon 7 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLP1R	ENST00000373256.5	c.780A>C	p.Leu260Phe	missense_variant	Exon 7 of 13	1	NM_002062.5	ENSP00000362353.4

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

GnomAD2 exomes AF: 0.565 AC: 141904 AN: 251338 AF XY: 0.563

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 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

African (AFR) AF: 0.575 AC: 19245 AN: 33468

American (AMR) AF: 0.611 AC: 27311 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 11905 AN: 26128

East Asian (EAS) AF: 0.524 AC: 20804 AN: 39696

South Asian (SAS) AF: 0.575 AC: 49558 AN: 86248

European-Finnish (FIN) AF: 0.550 AC: 29354 AN: 53384

Middle Eastern (MID) AF: 0.509 AC: 2933 AN: 5762

European-Non Finnish (NFE) AF: 0.566 AC: 628640 AN: 1111460

Other (OTH) AF: 0.555 AC: 33507 AN: 60376

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

African (AFR) AF: 0.574 AC: 23788 AN: 41432

American (AMR) AF: 0.580 AC: 8869 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1653 AN: 3466

East Asian (EAS) AF: 0.547 AC: 2821 AN: 5160

South Asian (SAS) AF: 0.588 AC: 2820 AN: 4792

European-Finnish (FIN) AF: 0.538 AC: 5690 AN: 10578

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38266 AN: 67948

Other (OTH) AF: 0.562 AC: 1183 AN: 2106

Alfa AF: 0.558 Hom.: 92079

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
PhyloP100		0.66
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042044; hg19: chr6-39041502; COSMIC: COSV107475465;