chr7-44191827-A-G

Variant names:

• chr7-44191827-A-G
• rs2908287
• ENST00000476008.1:n.480+5864T>C

Variant summary

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

The ENST00000476008.1(GCK):​n.480+5864T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 152,056 control chromosomes in the GnomAD database, including 45,856 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 0.78 (45856 hom., cov: 31)
• Consequence: GCK ENST00000476008.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.172
• 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: 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 = 0.828 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000476008.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000476008.1	TSL:5	n.480+5864T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.776 AC: 117876 AN: 151936 Hom.: 45817 Cov.: 31

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.829

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.710

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.760

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

GnomAD4 genome AF: 0.776 AC: 117974 AN: 152056 Hom.: 45856 Cov.: 31 AF XY: 0.778 AC XY: 57783 AN XY: 74318

African (AFR) AF: 0.835 AC: 34646 AN: 41482

American (AMR) AF: 0.757 AC: 11564 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2530 AN: 3466

East Asian (EAS) AF: 0.829 AC: 4288 AN: 5172

South Asian (SAS) AF: 0.780 AC: 3755 AN: 4816

European-Finnish (FIN) AF: 0.755 AC: 7970 AN: 10558

Middle Eastern (MID) AF: 0.705 AC: 206 AN: 292

European-Non Finnish (NFE) AF: 0.747 AC: 50751 AN: 67972

Other (OTH) AF: 0.763 AC: 1610 AN: 2110

Alfa AF: 0.692 Hom.: 2211

Bravo AF: 0.778

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.6
DANN	Benign	0.73
PhyloP100		-0.17

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2908287; hg19: chr7-44231426;