7-44156470-C-T

Variant names:

• chr7-44156470-C-T
• rs4724290
• NM_000162.5:c.46-3007G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000162.5(GCK):​c.46-3007G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 152,046 control chromosomes in the GnomAD database, including 15,374 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 0.41 (15374 hom., cov: 33)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• Publications: 2 publications found

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]

GCK Gene-Disease associations (from GenCC):

• hyperinsulinism due to glucokinase deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.46-3007G>A		intron_variant	Intron 1 of 9	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.48+2603G>A		intron_variant	Intron 1 of 9		NP_277042.1
GCK	NM_033508.3	c.42+1603G>A		intron_variant	Intron 2 of 10		NP_277043.1
GCK	NM_001354800.1	c.46-3007G>A		intron_variant	Intron 1 of 10		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.46-3007G>A		intron_variant	Intron 1 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62845 AN: 151928 Hom.: 15336 Cov.: 33

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.373

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

GnomAD4 genome AF: 0.414 AC: 62942 AN: 152046 Hom.: 15374 Cov.: 33 AF XY: 0.412 AC XY: 30643 AN XY: 74330

African (AFR) AF: 0.695 AC: 28805 AN: 41450

American (AMR) AF: 0.352 AC: 5381 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1021 AN: 3470

East Asian (EAS) AF: 0.466 AC: 2411 AN: 5172

South Asian (SAS) AF: 0.242 AC: 1166 AN: 4822

European-Finnish (FIN) AF: 0.324 AC: 3423 AN: 10574

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19562 AN: 67966

Other (OTH) AF: 0.372 AC: 787 AN: 2114

Alfa AF: 0.336 Hom.: 2004

Bravo AF: 0.433

Asia WGS AF: 0.370 AC: 1286 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4724290; hg19: chr7-44196069;