7-44189469-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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=-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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.-516G>A		upstream_gene_variant		ENST00000403799.8	NP_000153.1
GCK	NM_001354800.1	c.-516G>A		upstream_gene_variant			NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.-516G>A		upstream_gene_variant		1	NM_000162.5	ENSP00000384247.3

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

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.201

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0905

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.149

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

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.135

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.202

Alfa AF: 0.175 Hom.: 2887

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1799884; hg19: chr7-44229068;