rs1400535021

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000162.5(GCK):c.1155delG(p.Leu386TrpfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G385G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GCK
NM_000162.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:7O:1

Conservation

PhyloP100: -0.317

Publications

2 publications found

Variant links:

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

GCK links:

ENSG00000300758 (HGNC:):

ENSG00000300758 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 7-44145594-GC-G is Pathogenic according to our data. Variant chr7-44145594-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 503699.Status of the report is reviewed_by_expert_panel, 3 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GCK	NM_000162.5	MANE Select	c.1155delG	p.Leu386TrpfsTer16	frameshift	Exon 9 of 10	NP_000153.1
GCK	NM_033507.3		c.1158delG	p.Leu387TrpfsTer16	frameshift	Exon 9 of 10	NP_277042.1
GCK	NM_033508.3		c.1152delG	p.Leu385TrpfsTer16	frameshift	Exon 10 of 11	NP_277043.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GCK	ENST00000403799.8	TSL:1 MANE Select	c.1155delG	p.Leu386TrpfsTer16	frameshift	Exon 9 of 10	ENSP00000384247.3
GCK	ENST00000395796.8	TSL:1	n.*1153delG		non_coding_transcript_exon	Exon 10 of 11	ENSP00000379142.4
GCK	ENST00000459642.1	TSL:1	n.535delG		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000431

AC:

AN:

231862

AF XY:

0.00000788

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453800

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723084

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33380

American (AMR)

AF:

0.00

AC:

AN:

44156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.00

AC:

AN:

85498

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109994

Other (OTH)

AF:

0.0000166

AC:

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

May 11, 2020

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation, as the last 80 amino acids are replaced with 15 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23771925)

Aug 31, 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.Leu386Trpfs*16) 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 present in population databases (no rsID available, 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: 23771925, 32533152). ClinVar contains an entry for this variant (Variation ID: 503699). For these reasons, this variant has been classified as Pathogenic.

Permanent neonatal diabetes mellitus 1

Pathogenic:1

Jul 06, 2022

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Type 2 diabetes mellitus

Pathogenic:1

Jul 06, 2022

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Maturity-onset diabetes of the young type 2

Pathogenic:1

Jul 06, 2022

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Monogenic diabetes

Pathogenic:1

Sep 26, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.1155del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 386 in NM_000162.5, adding 15 novel amino acids before encountering a stop codon (p.(Leu386TrpfsTer16)). This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to the presence of only 1 copy in any subpopulation, thereby meeting ClinGen MDEP threshold criteria for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with two informative meioses in two families (PP1; internal lab contributors). In summary, c.1155del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PVS1, PM2_supporting, PS4_moderate, PP4_moderate, PP1.

Hyperinsulinism due to glucokinase deficiency

Pathogenic:1

Jul 06, 2022

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Maturity onset diabetes mellitus in young

Other:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain risk allele

Review Status:flagged submission

Collection Method:research

Potent mutations in GCK gene is associated with poor secretion of insulin. It is associated with milder forms of diabetes, which can be controlled by diet. However, there is no sufficient evidence to ascertain the significance of rs1400535021 in MODY, yet.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.32

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over