ENST00000476008.1:n.480+8222G>A

Variant names:

• chr7-44189469-C-T
• rs1799884
• ENST00000476008.1:n.480+8222G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The ENST00000476008.1(GCK):​n.480+8222G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 199,940 control chromosomes in the GnomAD database, including 2,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2204 hom., cov: 33)
  • Exomes 𝑓: 0.14 (579 hom.)
• Consequence: GCK ENST00000476008.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.555
• Publications: 202 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=-0.25).
• BP6: Variant 7-44189469-C-T is Benign according to our data. Variant chr7-44189469-C-T is described in ClinVar as Benign. ClinVar VariationId is 1258742.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.19 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.-516G>A		upstream_gene	N/A	NP_000153.1
	GCK	NM_001354800.1		c.-516G>A		upstream_gene	N/A	NP_001341729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000476008.1	TSL:5	n.480+8222G>A		intron	N/A
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.-516G>A		upstream_gene	N/A	ENSP00000384247.3
	GCK	ENST00000671824.1		c.-516G>A		upstream_gene	N/A	ENSP00000500264.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25879 AN: 152068 Hom.: 2200 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.204

GnomAD4 exome AF: 0.141 AC: 6757 AN: 47754 Hom.: 579 Cov.: 0 AF XY: 0.141 AC XY: 3486 AN XY: 24720

African (AFR) AF: 0.137 AC: 246 AN: 1792

American (AMR) AF: 0.201 AC: 745 AN: 3710

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 139 AN: 946

East Asian (EAS) AF: 0.153 AC: 482 AN: 3158

South Asian (SAS) AF: 0.112 AC: 656 AN: 5860

European-Finnish (FIN) AF: 0.0905 AC: 148 AN: 1636

Middle Eastern (MID) AF: 0.182 AC: 28 AN: 154

European-Non Finnish (NFE) AF: 0.141 AC: 3961 AN: 28134

Other (OTH) AF: 0.149 AC: 352 AN: 2364

GnomAD4 genome AF: 0.170 AC: 25890 AN: 152186 Hom.: 2204 Cov.: 33 AF XY: 0.167 AC XY: 12464 AN XY: 74434

African (AFR) AF: 0.173 AC: 7199 AN: 41514

American (AMR) AF: 0.196 AC: 2993 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 596 AN: 3472

East Asian (EAS) AF: 0.177 AC: 918 AN: 5178

South Asian (SAS) AF: 0.135 AC: 653 AN: 4824

European-Finnish (FIN) AF: 0.108 AC: 1149 AN: 10606

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.171 AC: 11639 AN: 67984

Other (OTH) AF: 0.202 AC: 426 AN: 2112

Alfa AF: 0.173 Hom.: 7022

Bravo AF: 0.181

Asia WGS AF: 0.130 AC: 455 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24520939, 8603762, 19018513, 16186409, 15677518, 15173029, 21697023)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.72
PhyloP100		0.56
PromoterAI		0.037	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1799884; hg19: chr7-44229068;