2-162149117-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002054.5(GCG):c.62G>T(p.Arg21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GCG NM_002054.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.177

Genes affected

GCG (HGNC:4191): (glucagon) The protein encoded by this gene is actually a preproprotein that is cleaved into four distinct mature peptides. One of these, glucagon, is a pancreatic hormone that counteracts the glucose-lowering action of insulin by stimulating glycogenolysis and gluconeogenesis. Glucagon is a ligand for a specific G-protein linked receptor whose signalling pathway controls cell proliferation. Two of the other peptides are secreted from gut endocrine cells and promote nutrient absorption through distinct mechanisms. Finally, the fourth peptide is similar to glicentin, an active enteroglucagon. [provided by RefSeq, Jul 2008]

LOC101929532 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07780966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCG	NM_002054.5	c.62G>T	p.Arg21Leu	missense_variant	2/6	ENST00000418842.7
LOC101929532	NR_110255.1	n.93-12653C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCG	ENST00000418842.7	c.62G>T	p.Arg21Leu	missense_variant	2/6	1	NM_002054.5	P1
GCG	ENST00000375497.3	c.62G>T	p.Arg21Leu	missense_variant	2/6	5		P1
GCG	ENST00000492913.1	n.151G>T		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459152 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2022

The c.62G>T (p.R21L) alteration is located in exon 2 (coding exon 1) of the GCG gene. This alteration results from a G to T substitution at nucleotide position 62, causing the arginine (R) at amino acid position 21 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.5
Dann	Benign	0.85
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.10	N
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.92	N;N
REVEL	Benign	0.12
Sift	Benign	0.65	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.0	B;B
Vest4		0.20
MutPred		0.37		Loss of MoRF binding (P = 0.0444);Loss of MoRF binding (P = 0.0444);
MVP		0.47
MPC		0.043
ClinPred		0.17	T
GERP RS		2.1
Varity_R		0.047
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs745474532; hg19: chr2-163005627;