6-39048860-C-T

Variant names:

• chr6-39048860-C-T
• rs10305420
• NM_002062.5:c.20C>T

Variant summary

Our verdict is Benign. The variant received -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. 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 0.28 (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
• Publications: 59 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=0.0019919574).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002062.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLP1R	NM_002062.5	MANE Select	c.20C>T	p.Pro7Leu	missense	Exon 1 of 13	NP_002053.3
	GLP1R	NR_136562.2		n.80C>T		non_coding_transcript_exon	Exon 1 of 14
	GLP1R	NR_136563.2		n.80C>T		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLP1R	ENST00000373256.5	TSL:1 MANE Select	c.20C>T	p.Pro7Leu	missense	Exon 1 of 13	ENSP00000362353.4	P43220

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

GnomAD2 exomes AF: 0.314 AC: 36162 AN: 114986 AF XY: 0.314

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 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

African (AFR) AF: 0.0670 AC: 1818 AN: 27136

American (AMR) AF: 0.270 AC: 9206 AN: 34078

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 8970 AN: 23654

East Asian (EAS) AF: 0.168 AC: 5075 AN: 30220

South Asian (SAS) AF: 0.199 AC: 15063 AN: 75680

European-Finnish (FIN) AF: 0.401 AC: 13661 AN: 34072

Middle Eastern (MID) AF: 0.379 AC: 1757 AN: 4632

European-Non Finnish (NFE) AF: 0.389 AC: 411001 AN: 1055390

Other (OTH) AF: 0.343 AC: 19164 AN: 55804

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

African (AFR) AF: 0.0772 AC: 3208 AN: 41572

American (AMR) AF: 0.299 AC: 4573 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1279 AN: 3470

East Asian (EAS) AF: 0.144 AC: 740 AN: 5154

South Asian (SAS) AF: 0.192 AC: 926 AN: 4830

European-Finnish (FIN) AF: 0.398 AC: 4217 AN: 10590

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.382 AC: 25971 AN: 67946

Other (OTH) AF: 0.284 AC: 601 AN: 2114

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 v4.9

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
PhyloP100		-0.58
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
PromoterAI		0.16	Neutral
Varity_R		0.031
gMVP		0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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