rs10305420

Positions:

• chr6-39048860-C-T

Variant summary

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

The NM_002062.5(GLP1R):​c.20C>T​(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,492,840 control chromosomes in the GnomAD database, including 99,598 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 0.28 (7298 hom., cov: 33)
  • Exomes 𝑓: 0.36 (92300 hom.)
• Consequence: GLP1R NM_002062.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.579

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=0.0019919574).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLP1R	NM_002062.5	c.20C>T	p.Pro7Leu	missense_variant	1/13	ENST00000373256.5
GLP1R	NR_136562.2	n.80C>T		non_coding_transcript_exon_variant	1/14
GLP1R	NR_136563.2	n.80C>T		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLP1R	ENST00000373256.5	c.20C>T	p.Pro7Leu	missense_variant	1/13	1	NM_002062.5	P1

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41868 AN: 152062 Hom.: 7296 Cov.: 33

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.288

GnomAD3 exomes AF: 0.314 AC: 36162 AN: 114986 Hom.: 6186 AF XY: 0.314 AC XY: 20706 AN XY: 66020

Gnomad AFR exome AF: 0.0733

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.379

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.397

Gnomad OTH exome AF: 0.359

GnomAD4 exome AF: 0.362 AC: 485715 AN: 1340666 Hom.: 92300 Cov.: 26 AF XY: 0.359 AC XY: 238369 AN XY: 664558

Gnomad4 AFR exome AF: 0.0670

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.401

Gnomad4 NFE exome AF: 0.389

Gnomad4 OTH exome AF: 0.343

GnomAD4 genome AF: 0.275 AC: 41860 AN: 152174 Hom.: 7298 Cov.: 33 AF XY: 0.275 AC XY: 20456 AN XY: 74402

Gnomad4 AFR AF: 0.0772

Gnomad4 AMR AF: 0.299

Gnomad4 ASJ AF: 0.369

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.382

Gnomad4 OTH AF: 0.284

Alfa AF: 0.331 Hom.: 1897

Bravo AF: 0.259

TwinsUK AF: 0.401 AC: 1487

ALSPAC AF: 0.377 AC: 1454

ESP6500AA AF: 0.0627 AC: 186

ESP6500EA AF: 0.306 AC: 2034

ExAC AF: 0.263 AC: 27569

Asia WGS AF: 0.155 AC: 540 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.050
Sift	Benign	0.42	T
Sift4G	Benign	0.071	T
Polyphen		0.0010	B
Vest4		0.073
MPC		0.47
ClinPred		0.0056	T
GERP RS		1.3
Varity_R		0.031
gMVP		0.45

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: rs10305420; hg19: chr6-39016636; COSMIC: COSV64714159;