chr6-39065819-G-T

Position:

• chr6-39065819-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002062.5(GLP1R):​c.392G>T​(p.Arg131Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R131Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10955617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLP1R	NM_002062.5	c.392G>T	p.Arg131Leu	missense_variant	4/13	ENST00000373256.5	NP_002053.3
GLP1R	NR_136562.2	n.452G>T		non_coding_transcript_exon_variant	4/14
GLP1R	NR_136563.2	n.452G>T		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>T	p.Arg131Leu	missense_variant	4/13	1	NM_002062.5	ENSP00000362353	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.97	P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.12
Sift	Benign	0.26	T
Sift4G	Benign	0.26	T
Polyphen		0.021	B
Vest4		0.30
MutPred		0.42		Gain of catalytic residue at R131 (P = 0.0618);
MVP		0.60
MPC		0.58
ClinPred		0.16	T
GERP RS		0.78
Varity_R		0.15
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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;