7-44149794-G-T

Variant names:

• chr7-44149794-G-T
• rs144723656
• NM_000162.5:c.645C>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000162.5(GCK):​c.645C>A​(p.Tyr215*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y215Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCK NM_000162.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -2.27
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinism due to glucokinase deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC105375258 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-44149794-G-T is Pathogenic according to our data. Variant chr7-44149794-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 453007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000162.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.645C>A	p.Tyr215*	stop_gained	Exon 6 of 10	NP_000153.1
	GCK	NM_033507.3		c.648C>A	p.Tyr216*	stop_gained	Exon 6 of 10	NP_277042.1
	GCK	NM_033508.3		c.642C>A	p.Tyr214*	stop_gained	Exon 7 of 11	NP_277043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.645C>A	p.Tyr215*	stop_gained	Exon 6 of 10	ENSP00000384247.3
	GCK	ENST00000395796.8	TSL:1	n.*643C>A		non_coding_transcript_exon	Exon 7 of 11	ENSP00000379142.4
	GCK	ENST00000395796.8	TSL:1	n.*643C>A		3_prime_UTR	Exon 7 of 11	ENSP00000379142.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461830 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:2

Aug 02, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y215* pathogenic mutation (also known as c.645C>A), located in coding exon 6 of the GCK gene, results from a C to A substitution at nucleotide position 645. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in several individuals with maturity-onset diabetes of the young (Thomson KL et al. Hum Mutat, 2003 Nov;22:417; Sagen JV et al. Pediatr Diabetes, 2008 Oct;9:442-9; Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971; Patel KA et al. Diabetologia, 2022 Feb;65:336-342). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Aug 29, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr214X variant in GCK has been reported (as p.Tyr215X) in 1 individual wi th clinical features of gestational diabetes (Ellard 2000). This variant has als o been reported in ClinVar (Variation ID# 453007) and is absent from the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This nonsense v ariant leads to a premature termination codon, which is predicted to lead to a t runcated or absent protein. Heterozygous loss of function of the GCK gene is an established disease mechanism in MODY. In summary, although additional studies a re required to fully establish its clinical significance, the p.Tyr214X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.

not provided Pathogenic:2

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr215*) in the GCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCK are known to be pathogenic (PMID: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of maturity-onset diabetes of the young (PMID: 30592380). ClinVar contains an entry for this variant (Variation ID: 453007). For these reasons, this variant has been classified as Pathogenic.

Apr 19, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36257325, 30592380, 34686905, 32533152)

Monogenic diabetes Pathogenic:1

May 06, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCK c.645C>A (p.Tyr215X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251450 control chromosomes (gnomAD). c.645C>A has been observed in individuals affected with Monogenic Diabetes (Wang_2019, Caswell_2020). These data indicate that the variant may be associated with disease. 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: 14517956, 14517946, 16731834, 32533152, 30592380). ClinVar contains an entry for this variant (Variation ID: 453007). Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Benign	0.96
Eigen	Benign	-0.75
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
PhyloP100		-2.3
Vest4		0.96
GERP RS		-11
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs144723656; hg19: chr7-44189393;