17-81810878-G-A

Position:

chr17-81810878-G-A

Variant summary

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

The NM_000160.5(GCGR):c.217G>A(p.Ala73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,502,590 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

GCGR
NM_000160.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.92

Variant links:

Genes affected

GCGR (HGNC:4192): (glucagon receptor) The protein encoded by this gene is a glucagon receptor that is important in controlling blood glucose levels. Defects in this gene are a cause of non-insulin-dependent diabetes mellitus (NIDDM).[provided by RefSeq, Jan 2010]

GCGR links:

GCGR (HGNC:):

GCGR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCGR	NM_000160.5 linkuse as main transcript	c.217G>A	p.Ala73Thr	missense_variant	4/14	ENST00000400723.8	NP_000151.1	P47871
GCGR	XM_006722277.2 linkuse as main transcript	c.217G>A	p.Ala73Thr	missense_variant	4/14		XP_006722340.1	P47871
GCGR	XM_017024446.2 linkuse as main transcript	c.211G>A	p.Ala71Thr	missense_variant	4/14		XP_016879935.1
GCGR	XM_011523539.2 linkuse as main transcript	c.141G>A	p.Pro47Pro	synonymous_variant	2/12		XP_011521841.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GCGR	ENST00000400723.8 linkuse as main transcript	c.217G>A	p.Ala73Thr	missense_variant	4/14	1	NM_000160.5	ENSP00000383558.3	P47871
GCGR	ENST00000570996.5 linkuse as main transcript	c.217G>A	p.Ala73Thr	missense_variant	4/12	2		ENSP00000460976.1	I3L454
GCGR	ENST00000573428.1 linkuse as main transcript	c.217G>A	p.Ala73Thr	missense_variant	4/4	4		ENSP00000458930.1	I3L1L8
GCGR	ENST00000574283.2 linkuse as main transcript	n.301G>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes

AF:

0.0000802

AC:

AN:

149566

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000199

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000705

AC:

AN:

141900

Hom.:

AF XY:

0.0000132

AC XY:

AN XY:

75908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000440

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000163

AC:

AN:

1353024

Hom.:

Cov.:

AF XY:

0.0000210

AC XY:

AN XY:

667702

show subpopulations

Gnomad4 AFR exome

AF:

0.000130

Gnomad4 AMR exome

AF:

0.0000577

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000506

Gnomad4 FIN exome

AF:

0.000265

Gnomad4 NFE exome

AF:

0.00000283

Gnomad4 OTH exome

AF:

0.0000179

GnomAD4 genome

AF:

0.0000802

AC:

AN:

149566

Hom.:

Cov.:

AF XY:

0.0000822

AC XY:

AN XY:

73020

show subpopulations

Gnomad4 AFR

AF:

0.000219

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000199

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the GCGR protein (p.Ala73Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GCGR-related conditions. ClinVar contains an entry for this variant (Variation ID: 1991991). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.19

T;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.1

M;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.52

N;.;.

REVEL

Benign

0.22

Sift

Uncertain

0.0020

D;.;.

Sift4G

Uncertain

0.016

D;T;D

Polyphen

0.70

P;.;.

Vest4

0.18

MutPred

0.56

Gain of glycosylation at P72 (P = 0.1304);Gain of glycosylation at P72 (P = 0.1304);Gain of glycosylation at P72 (P = 0.1304);

MVP

0.79

MPC

0.0034

ClinPred

0.45

GERP RS

3.2

Varity_R

0.15

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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