chr7-44150869-T-G

Variant names:

• chr7-44150869-T-G
• rs2268573
• NM_000162.5:c.483+87A>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.483+87A>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 1,601,364 control chromosomes in the GnomAD database, including 208,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (25911 hom., cov: 33)
  • Exomes 𝑓: 0.50 (182832 hom.)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.37

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=-0.91).
• BP6: Variant 7-44150869-T-G is Benign according to our data. Variant chr7-44150869-T-G is described in ClinVar as [Benign]. Clinvar id is 676858.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.483+87A>C		intron_variant	Intron 4 of 9	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.486+87A>C		intron_variant	Intron 4 of 9		NP_277042.1
GCK	NM_033508.3	c.480+87A>C		intron_variant	Intron 5 of 10		NP_277043.1
GCK	NM_001354800.1	c.483+87A>C		intron_variant	Intron 4 of 10		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.483+87A>C		intron_variant	Intron 4 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87106 AN: 151982 Hom.: 25887 Cov.: 33

Gnomad AFR AF: 0.741

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.559

GnomAD4 exome AF: 0.499 AC: 723248 AN: 1449266 Hom.: 182832 AF XY: 0.496 AC XY: 357698 AN XY: 720986

Gnomad4 AFR exome AF: 0.745

Gnomad4 AMR exome AF: 0.594

Gnomad4 ASJ exome AF: 0.496

Gnomad4 EAS exome AF: 0.636

Gnomad4 SAS exome AF: 0.430

Gnomad4 FIN exome AF: 0.499

Gnomad4 NFE exome AF: 0.488

Gnomad4 OTH exome AF: 0.504

GnomAD4 genome AF: 0.573 AC: 87174 AN: 152098 Hom.: 25911 Cov.: 33 AF XY: 0.572 AC XY: 42507 AN XY: 74352

Gnomad4 AFR AF: 0.741

Gnomad4 AMR AF: 0.568

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.633

Gnomad4 SAS AF: 0.435

Gnomad4 FIN AF: 0.493

Gnomad4 NFE AF: 0.495

Gnomad4 OTH AF: 0.558

Alfa AF: 0.538 Hom.: 3753

Bravo AF: 0.589

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

Jun 20, 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	-0.91
CADD	Benign	0.37
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2268573; hg19: chr7-44190468;