6-39065754-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_002062.5(GLP1R):c.327C>T(p.Leu109=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,583,028 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0089 (27 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (18 hom.)
• Consequence: GLP1R NM_002062.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.691

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 6-39065754-C-T is Benign according to our data. Variant chr6-39065754-C-T is described in ClinVar as [Benign]. Clinvar id is 712621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.691 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00888 (1353/152324) while in subpopulation AFR AF= 0.0303 (1260/41576). AF 95% confidence interval is 0.0289. There are 27 homozygotes in gnomad4. There are 640 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1351 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLP1R	NM_002062.5	c.327C>T	p.Leu109=	synonymous_variant	4/13	ENST00000373256.5
GLP1R	NR_136562.2	n.387C>T		non_coding_transcript_exon_variant	4/14
GLP1R	NR_136563.2	n.387C>T		non_coding_transcript_exon_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLP1R	ENST00000373256.5	c.327C>T	p.Leu109=	synonymous_variant	4/13	1	NM_002062.5	P1

Frequencies

GnomAD3 genomes AF: 0.00888 AC: 1351 AN: 152206 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00232 AC: 464 AN: 199882 Hom.: 6 AF XY: 0.00165 AC XY: 176 AN XY: 106714

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000574

Gnomad NFE exome AF: 0.0000575

Gnomad OTH exome AF: 0.000968

GnomAD4 exome AF: 0.000944 AC: 1350 AN: 1430704 Hom.: 18 Cov.: 31 AF XY: 0.000829 AC XY: 587 AN XY: 708312

Gnomad4 AFR exome AF: 0.0311

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000491

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.0000657

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00888 AC: 1353 AN: 152324 Hom.: 27 Cov.: 33 AF XY: 0.00859 AC XY: 640 AN XY: 74472

Gnomad4 AFR AF: 0.0303

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00473 Hom.: 4

Bravo AF: 0.0103

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 09, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	4.4
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs146487412; hg19: chr6-39033530;