rs758989

Variant names:

• chr7-44163407-C-T
• rs758989
• NM_000162.5:c.46-9944G>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.46-9944G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 152,072 control chromosomes in the GnomAD database, including 29,328 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 0.61 (29328 hom., cov: 33)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 16 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000162.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.46-9944G>A		intron	N/A	NP_000153.1	Q53Y25
	GCK	NM_001354800.1		c.46-9944G>A		intron	N/A	NP_001341729.1	A0A5F9ZGW4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.46-9944G>A		intron	N/A	ENSP00000384247.3	P35557-1
	GCK	ENST00000671824.1		c.46-9944G>A		intron	N/A	ENSP00000500264.1	A0A5F9ZHE0
	GCK	ENST00000673284.1		c.46-9944G>A		intron	N/A	ENSP00000499852.1	A0A5F9ZGW4

Frequencies

GnomAD3 genomes AF: 0.606 AC: 92118 AN: 151956 Hom.: 29291 Cov.: 33

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.658

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.582

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

GnomAD4 genome AF: 0.606 AC: 92200 AN: 152072 Hom.: 29328 Cov.: 33 AF XY: 0.606 AC XY: 45018 AN XY: 74306

African (AFR) AF: 0.814 AC: 33760 AN: 41494

American (AMR) AF: 0.580 AC: 8859 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1751 AN: 3468

East Asian (EAS) AF: 0.658 AC: 3408 AN: 5178

South Asian (SAS) AF: 0.424 AC: 2044 AN: 4822

European-Finnish (FIN) AF: 0.553 AC: 5843 AN: 10560

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34712 AN: 67950

Other (OTH) AF: 0.579 AC: 1226 AN: 2116

Alfa AF: 0.533 Hom.: 21321

Bravo AF: 0.622

Asia WGS AF: 0.534 AC: 1857 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.41
DANN	Benign	0.70
PhyloP100		-1.7
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: rs758989; hg19: chr7-44203006;