17-81809839-G-A

Position:

• chr17-81809839-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000160.5(GCGR):​c.118G>A​(p.Gly40Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00808 in 1,536,594 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0083 (71 hom.)
• Consequence: GCGR NM_000160.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.712

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02872321).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00826 (11438/1384256) while in subpopulation MID AF= 0.0372 (212/5696). AF 95% confidence interval is 0.0331. There are 71 homozygotes in gnomad4_exome. There are 5560 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCGR	NM_000160.5	c.118G>A	p.Gly40Ser	missense_variant	3/14	ENST00000400723.8	NP_000151.1
GCGR	XM_006722277.2	c.118G>A	p.Gly40Ser	missense_variant	3/14		XP_006722340.1
GCGR	XM_017024446.2	c.112G>A	p.Gly38Ser	missense_variant	3/14		XP_016879935.1
GCGR	XM_011523539.2	c.-109G>A		5_prime_UTR_variant	1/12		XP_011521841.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCGR	ENST00000400723.8	c.118G>A	p.Gly40Ser	missense_variant	3/14	1	NM_000160.5	ENSP00000383558.3

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 983 AN: 152220 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00740 AC: 1049 AN: 141720 Hom.: 4 AF XY: 0.00753 AC XY: 571 AN XY: 75862

Gnomad AFR exome AF: 0.00225

Gnomad AMR exome AF: 0.00679

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.0000942

Gnomad SAS exome AF: 0.00946

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00855

Gnomad OTH exome AF: 0.00972

GnomAD4 exome AF: 0.00826 AC: 11438 AN: 1384256 Hom.: 71 Cov.: 32 AF XY: 0.00814 AC XY: 5560 AN XY: 683062

Gnomad4 AFR exome AF: 0.00222

Gnomad4 AMR exome AF: 0.00681

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.0000840

Gnomad4 SAS exome AF: 0.00775

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00871

Gnomad4 OTH exome AF: 0.00948

GnomAD4 genome AF: 0.00645 AC: 982 AN: 152338 Hom.: 13 Cov.: 33 AF XY: 0.00614 AC XY: 457 AN XY: 74488

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00795

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00994 Hom.: 10

Bravo AF: 0.00759

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.0113 AC: 36

ExAC AF: 0.00582 AC: 142

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	GCGR: BP4, BS2 -

Type 2 diabetes mellitus Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Feb 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.4
DANN	Benign	0.88
DEOGEN2	Benign	0.034	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.28	T;T;T
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.61	N;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.4	N;.;.
REVEL	Benign	0.028
Sift	Benign	0.38	T;.;.
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.10
MVP		0.43
MPC		0.0026
ClinPred		0.00042	T
GERP RS		-1.3
Varity_R		0.10
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1801483; hg19: chr17-79767715; COSMIC: COSV105339528; COSMIC: COSV105339528;