rs2268575

Positions:

• chr7-44149675-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

LOC105375258 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.679+85A>G		intron_variant		ENST00000403799.8	NP_000153.1
LOC105375258	XR_927223.3	n.220-14T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.679+85A>G		intron_variant		1	NM_000162.5	ENSP00000384247	P1

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

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.230

Gnomad4 FIN exome AF: 0.182

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.191

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

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.180

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.205

Alfa AF: 0.191 Hom.: 2346

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.2
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs2268575; hg19: chr7-44189274;