rs12673242

chr7-44167895-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000162.5(GCK):c.46-14432A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 152,050 control chromosomes in the GnomAD database, including 3,951 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3951 hom., cov: 32)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.966

Genes affected

GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.46-14432A>G		intron_variant		ENST00000403799.8
GCK	NM_001354800.1	c.46-14432A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.46-14432A>G		intron_variant		1	NM_000162.5	P1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31743 AN: 151934 Hom.: 3941 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.169

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.209 AC: 31791 AN: 152050 Hom.: 3951 Cov.: 32 AF XY: 0.207 AC XY: 15369 AN XY: 74324

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.180

Gnomad4 EAS AF: 0.286

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.168

Alfa AF: 0.180 Hom.: 659

Bravo AF: 0.216

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	1.4
Dann	Benign	0.45

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: rs12673242; hg19: chr7-44207494;