rs150914617

chr7-44146445-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000162.5(GCK):c.1019+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,600,426 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (19 hom.)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.922

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-44146445-C-T is Benign according to our data. Variant chr7-44146445-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44146445-C-T is described in Lovd as [Likely_benign]. Variant chr7-44146445-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00309 (471/152286) while in subpopulation NFE AF= 0.00547 (372/68012). AF 95% confidence interval is 0.00501. There are 2 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.1019+18G>A		intron_variant		ENST00000403799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.1019+18G>A		intron_variant		1	NM_000162.5	P1

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152168 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00547

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00315 AC: 752 AN: 238614 Hom.: 1 AF XY: 0.00308 AC XY: 402 AN XY: 130428

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00503

Gnomad NFE exome AF: 0.00517

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00412 AC: 5966 AN: 1448140 Hom.: 19 Cov.: 33 AF XY: 0.00403 AC XY: 2909 AN XY: 720946

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00450

Gnomad4 NFE exome AF: 0.00490

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.00309 AC: 471 AN: 152286 Hom.: 2 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74464

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00547

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00323 Hom.: 1

Bravo AF: 0.00275

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 03, 2023	Variant summary: GCK c.1019+18G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Three computational tools predict that the variant abolishes a cryptic 5' splicing donor site but does not affect the canonical splice site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0032 in 239030 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 126-fold of the estimated maximal expected allele frequency for a pathogenic variant in GCK causing Monogenic Diabetes phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1019+18G>A has been reported in the literature in individuals affected with diabetes and hyperinsulinism without evidence of cosegregation with disease (e.g. Lehto_1999, Johansen_2005, Lukasova_2008, Odem_2009, Snider_2013). These reports do not provide unequivocal conclusions about association of the variant with Monogenic Diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10447526, 14517946, 15928245, 18271687, 19515026, 23275527). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2020	The c.1016+18G>A variant in GCK classified as benign because it has been identified in 0.5% (660/125912) of European chromosomes, including 2 homozygote occurences, by gnomAD (http://gnomad.broadinstitute.org). In additon, it is not located within the splice consensus sequence and computational splice prediction tools predict disruption of a cryptic splice at this position without effect on the canonical splice. It has been reported in ClinVar (Variation ID: 377918). ACMG/AMP Criteria applied: BS1, BP4, BP7. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2016	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. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	GCK: BP4 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinism due to glucokinase deficiency;C5393570:Permanent neonatal diabetes mellitus 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.1
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs150914617; hg19: chr7-44186044;