rs2268574

chr7-44149722-A-Gchr7-44149722-A-T

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+38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,592,566 control chromosomes in the GnomAD database, including 207,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (25486 hom., cov: 32)
  • Exomes 𝑓: 0.50 (181745 hom.)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.77

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=-0.9).
• BP6: Variant 7-44149722-A-G is Benign according to our data. Variant chr7-44149722-A-G is described in ClinVar as [Benign]. Clinvar id is 673534.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-44149722-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.679+38T>C		intron_variant		ENST00000403799.8
LOC105375258	XR_927223.3	n.253A>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.679+38T>C		intron_variant		1	NM_000162.5	P1

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86483 AN: 151798 Hom.: 25462 Cov.: 32

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.558

GnomAD3 exomes AF: 0.531 AC: 132823 AN: 250270 Hom.: 36046 AF XY: 0.518 AC XY: 70099 AN XY: 135390

Gnomad AFR exome AF: 0.732

Gnomad AMR exome AF: 0.595

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.661

Gnomad SAS exome AF: 0.435

Gnomad FIN exome AF: 0.497

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.527

GnomAD4 exome AF: 0.499 AC: 718976 AN: 1440652 Hom.: 181745 Cov.: 26 AF XY: 0.496 AC XY: 356115 AN XY: 717960

Gnomad4 AFR exome AF: 0.735

Gnomad4 AMR exome AF: 0.593

Gnomad4 ASJ exome AF: 0.498

Gnomad4 EAS exome AF: 0.631

Gnomad4 SAS exome AF: 0.431

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.488

Gnomad4 OTH exome AF: 0.504

GnomAD4 genome AF: 0.570 AC: 86554 AN: 151914 Hom.: 25486 Cov.: 32 AF XY: 0.569 AC XY: 42208 AN XY: 74226

Gnomad4 AFR AF: 0.729

Gnomad4 AMR AF: 0.567

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.630

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.495

Gnomad4 NFE AF: 0.495

Gnomad4 OTH AF: 0.557

Alfa AF: 0.536 Hom.: 4572

Bravo AF: 0.585

Asia WGS AF: 0.524 AC: 1822 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 20, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.19
Dann	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2268574; hg19: chr7-44189321; COSMIC: COSV60787932; COSMIC: COSV60787932;