chr7-44145489-G-A

Position:

• chr7-44145489-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000162.5(GCK):​c.1253+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,592,264 control chromosomes in the GnomAD database, including 47,418 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11807 hom., cov: 34)
  • Exomes 𝑓: 0.20 (35611 hom.)
• Consequence: GCK NM_000162.5 splice_region, intron
• Scores: Splicing: ADA: 0.0009073
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.451

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]

GCK (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 7-44145489-G-A is Benign according to our data. Variant chr7-44145489-G-A is described in ClinVar as [Benign]. Clinvar id is 129147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44145489-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.1253+8C>T		splice_region_variant, intron_variant		ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1253+8C>T		splice_region_variant, intron_variant		1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50947 AN: 152062 Hom.: 11776 Cov.: 34

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.279

GnomAD3 exomes AF: 0.270 AC: 59821 AN: 221712 Hom.: 9843 AF XY: 0.259 AC XY: 31194 AN XY: 120660

Gnomad AFR exome AF: 0.672

Gnomad AMR exome AF: 0.311

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.433

Gnomad SAS exome AF: 0.289

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.202 AC: 291080 AN: 1440084 Hom.: 35611 Cov.: 33 AF XY: 0.203 AC XY: 144864 AN XY: 713972

Gnomad4 AFR exome AF: 0.680

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.283

Gnomad4 FIN exome AF: 0.238

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.335 AC: 51020 AN: 152180 Hom.: 11807 Cov.: 34 AF XY: 0.337 AC XY: 25049 AN XY: 74402

Gnomad4 AFR AF: 0.658

Gnomad4 AMR AF: 0.283

Gnomad4 ASJ AF: 0.169

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.278

Alfa AF: 0.242 Hom.: 3831

Bravo AF: 0.353

Asia WGS AF: 0.330 AC: 1147 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Maturity onset diabetes mellitus in young Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 08, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	GCK gene is associated with poor secretion of insulin. Associated with milder forms of diabetes, which can be controlled by diet well. The association of this particular Variant(rs2908274) with MODY is also seen. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 18159847, 16378108) -

Maturity-onset diabetes of the young type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Transient Neonatal Diabetes, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Permanent neonatal diabetes mellitus Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hyperinsulinism due to glucokinase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.8
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00091
dbscSNV1_RF	Benign	0.0020
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: rs2908274; hg19: chr7-44185088; COSMIC: COSV56267403; COSMIC: COSV56267403;