17-81810848-G-A

Position:

chr17-81810848-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM1PM2PP3_Strong

The NM_000160.5(GCGR):c.187G>A(p.Asp63Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,536,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

GCGR
NM_000160.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.18

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 Pathogenic. Variant got 10 ACMG points.

PS1

Transcript NM_000160.5 (GCGR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a mutagenesis_site Abolishes glucagon binding. (size 0) in uniprot entity GLR_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCGR	NM_000160.5 linkuse as main transcript	c.187G>A	p.Asp63Asn	missense_variant	4/14	ENST00000400723.8	NP_000151.1	P47871
GCGR	XM_006722277.2 linkuse as main transcript	c.187G>A	p.Asp63Asn	missense_variant	4/14		XP_006722340.1	P47871
GCGR	XM_017024446.2 linkuse as main transcript	c.181G>A	p.Asp61Asn	missense_variant	4/14		XP_016879935.1
GCGR	XM_011523539.2 linkuse as main transcript	c.111G>A	p.Ser37Ser	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.187G>A	p.Asp63Asn	missense_variant	4/14	1	NM_000160.5	ENSP00000383558.3	P47871
GCGR	ENST00000570996.5 linkuse as main transcript	c.187G>A	p.Asp63Asn	missense_variant	4/12	2		ENSP00000460976.1	I3L454
GCGR	ENST00000573428.1 linkuse as main transcript	c.187G>A	p.Asp63Asn	missense_variant	4/4	4		ENSP00000458930.1	I3L1L8
GCGR	ENST00000574283.2 linkuse as main transcript	n.271G>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000352

AC:

AN:

141942

Hom.:

AF XY:

0.0000263

AC XY:

AN XY:

75932

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000941

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000166

AC:

AN:

1384488

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

683190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.0000841

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000579

Gnomad4 NFE exome

AF:

0.0000120

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

GCGR-related hyperglucagonemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 22, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 63 of the GCGR protein (p.Asp63Asn). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with hypercalcemia (PMID: 30032256). ClinVar contains an entry for this variant (Variation ID: 1064739). 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 disruptive. Experimental studies have shown that this missense change affects GCGR function (PMID: 30294546). 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

Pathogenic

0.85

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

D;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.5

M;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-4.3

D;.;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.025

D;.;.

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.87

MutPred

0.85

Loss of phosphorylation at T61 (P = 0.1311);Loss of phosphorylation at T61 (P = 0.1311);Loss of phosphorylation at T61 (P = 0.1311);

MVP

0.92

MPC

0.0090

ClinPred

0.94

GERP RS

4.2

Varity_R

0.91

gMVP

0.98

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