rs2268575

Variant names:

• chr7-44149675-T-C
• rs2268575
• NM_000162.5:c.679+85A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000162.5(GCK):​c.679+85A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,308,446 control chromosomes in the GnomAD database, including 24,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (2537 hom., cov: 32)
  • Exomes 𝑓: 0.19 (21586 hom.)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.102
• Publications: 24 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

ENSG00000300758 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-44149675-T-C is Benign according to our data. Variant chr7-44149675-T-C is described in ClinVar as Benign. ClinVar VariationId is 1248825.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.679+85A>G		intron_variant	Intron 6 of 9	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.679+85A>G		intron_variant	Intron 6 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27484 AN: 151860 Hom.: 2536 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.205

GnomAD4 exome AF: 0.191 AC: 220435 AN: 1156466 Hom.: 21586 AF XY: 0.193 AC XY: 113446 AN XY: 588908

African (AFR) AF: 0.143 AC: 3963 AN: 27664

American (AMR) AF: 0.228 AC: 9798 AN: 43026

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5232 AN: 24018

East Asian (EAS) AF: 0.155 AC: 5920 AN: 38112

South Asian (SAS) AF: 0.230 AC: 18204 AN: 79100

European-Finnish (FIN) AF: 0.182 AC: 8975 AN: 49338

Middle Eastern (MID) AF: 0.240 AC: 1226 AN: 5102

European-Non Finnish (NFE) AF: 0.188 AC: 157484 AN: 839688

Other (OTH) AF: 0.191 AC: 9633 AN: 50418

GnomAD4 genome AF: 0.181 AC: 27495 AN: 151980 Hom.: 2537 Cov.: 32 AF XY: 0.182 AC XY: 13551 AN XY: 74284

African (AFR) AF: 0.143 AC: 5936 AN: 41424

American (AMR) AF: 0.224 AC: 3427 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 734 AN: 3466

East Asian (EAS) AF: 0.167 AC: 860 AN: 5154

South Asian (SAS) AF: 0.229 AC: 1099 AN: 4802

European-Finnish (FIN) AF: 0.180 AC: 1905 AN: 10560

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.190 AC: 12883 AN: 67966

Other (OTH) AF: 0.205 AC: 432 AN: 2110

Alfa AF: 0.191 Hom.: 2779

Bravo AF: 0.181

Asia WGS AF: 0.191 AC: 668 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.2
DANN	Benign	0.62
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2268575; hg19: chr7-44189274;