Variant 6-39048854-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002062.5(GLP1R):c.14C>T(p.Pro5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,491,932 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

GLP1R
NM_002062.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0530

Variant links:

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]

GLP1R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12515068).

BS2

High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GLP1R	NM_002062.5 linkuse as main transcript	c.14C>T	p.Pro5Leu	missense_variant	1/13	ENST00000373256.5
GLP1R	NR_136562.2 linkuse as main transcript	n.74C>T		non_coding_transcript_exon_variant	1/14
GLP1R	NR_136563.2 linkuse as main transcript	n.74C>T		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLP1R	ENST00000373256.5 linkuse as main transcript	c.14C>T	p.Pro5Leu	missense_variant	1/13	1	NM_002062.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000236

AC:

AN:

114620

Hom.:

AF XY:

0.000244

AC XY:

AN XY:

65642

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000440

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000301

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000420

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000125

AC:

168

AN:

1339614

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

664000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000575

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000303

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.000304

GnomAD4 genome

AF:

0.000105

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000283

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.0000934

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.14C>T (p.P5L) alteration is located in exon 1 (coding exon 1) of the GLP1R gene. This alteration results from a C to T substitution at nucleotide position 14, causing the proline (P) at amino acid position 5 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.53

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.7

REVEL

Benign

0.034

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.21

MutPred

0.25

Loss of disorder (P = 0.026);

MVP

0.60

MPC

0.47

ClinPred

0.14

GERP RS

1.7

Varity_R

0.15

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over