NM_000162.5:c.46-6080G>A

Variant names:

• chr7-44159543-C-T
• rs1799831
• NM_000162.5:c.46-6080G>A

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.46-6080G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,100 control chromosomes in the GnomAD database, including 3,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (3684 hom., cov: 33)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.991

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-44159543-C-T is Benign according to our data. Variant chr7-44159543-C-T is described in ClinVar as [Benign]. Clinvar id is 676190.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.46-6080G>A		intron_variant	Intron 1 of 9	ENST00000403799.8	NP_000153.1
GCK	NM_001354800.1	c.46-6080G>A		intron_variant	Intron 1 of 10		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.46-6080G>A		intron_variant	Intron 1 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31500 AN: 151984 Hom.: 3677 Cov.: 33

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.172

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.207 AC: 31534 AN: 152100 Hom.: 3684 Cov.: 33 AF XY: 0.207 AC XY: 15414 AN XY: 74346

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.172

Alfa AF: 0.189 Hom.: 398

Bravo AF: 0.209

Asia WGS AF: 0.191 AC: 662 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.93
CADD	Benign	0.45
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1799831; hg19: chr7-44199142;