2-162144091-T-C

Position:

• chr2-162144091-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002054.5(GCG):​c.472A>G​(p.Ile158Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,612,636 control chromosomes in the GnomAD database, including 19 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (18 hom.)
• Consequence: GCG NM_002054.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.270

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]

GCG (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005893886).
• BP6: Variant 2-162144091-T-C is Benign according to our data. Variant chr2-162144091-T-C is described in ClinVar as [Benign]. Clinvar id is 718683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCG	NM_002054.5	c.472A>G	p.Ile158Val	missense_variant	5/6	ENST00000418842.7	NP_002045.1
LOC101929532	NR_110255.1	n.93-17679T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCG	ENST00000418842.7	c.472A>G	p.Ile158Val	missense_variant	5/6	1	NM_002054.5	ENSP00000387662.2
GCG	ENST00000375497.3	c.472A>G	p.Ile158Val	missense_variant	5/6	5		ENSP00000364647.3
GCG	ENST00000483769.1	n.325A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 329 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00268 AC: 667 AN: 248640 Hom.: 3 AF XY: 0.00290 AC XY: 391 AN XY: 134870

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000581

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00546

Gnomad FIN exome AF: 0.00845

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00255 AC: 3724 AN: 1460324 Hom.: 18 Cov.: 29 AF XY: 0.00266 AC XY: 1932 AN XY: 726546

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000739

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00634

Gnomad4 FIN exome AF: 0.00951

Gnomad4 NFE exome AF: 0.00224

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00215 AC: 328 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00255 AC XY: 190 AN XY: 74480

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.00782

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00124

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00170 AC: 14

ExAC AF: 0.00283 AC: 342

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00235

EpiControl AF: 0.00219

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.051
DANN	Benign	0.49
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.46	.;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.18	N;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.14
MVP		0.27
MPC		0.034
ClinPred		0.00060	T
GERP RS		-2.9
Varity_R		0.11
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs150179526; hg19: chr2-163000601;