Genetic Variant NM_002062.5:c.780A>T (chr6-39073726-A-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002062.5(GLP1R):c.780A>T(p.Leu260Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: not found (cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GLP1R
NM_002062.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.656

Publications

74 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06533489).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLP1R	NM_002062.5 link	c.780A>T	p.Leu260Phe	missense_variant	Exon 7 of 13	ENST00000373256.5	NP_002053.3	P43220A0A142FHB8
GLP1R	NR_136562.2 link	n.840A>T		non_coding_transcript_exon_variant	Exon 7 of 14
GLP1R	NR_136563.2 link	n.840A>T		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 link	c.780A>T	p.Leu260Phe	missense_variant	Exon 7 of 13	1	NM_002062.5	ENSP00000362353.4		P43220

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461722

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111890

Other (OTH)

AF:

0.000132

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

92079

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.035

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.074

DEOGEN2

Benign

0.19

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.25

M_CAP

Benign

0.0052

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.5

PhyloP100

0.66

PrimateAI

Uncertain

0.62

PROVEAN

Benign

3.4

REVEL

Benign

0.054

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.024

MutPred

0.56

Gain of glycosylation at S258 (P = 0.1894);

MVP

0.38

MPC

0.51

ClinPred

0.031

GERP RS

3.9

Varity_R

0.063

gMVP

0.37

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over