chr7-44153465-T-C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM2_SupportingPVS1PP4_ModeratePS4PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.46-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 1 of NM_000162.5. This variant is predicted to cause an in-frame deletion of part of biologically-relevant exon 2 of 10, a region important for protein function (PVS1; PMID:19790256). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMIDs: 17573900, 27256595, 30447144; internal lab contributors). Furthermore, at least three of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID:27256595, 30447144; internal lab contributors). This variant segregated with hyperglycemia with 5 informative meioses in 5 families (PP1_Strong; PMIDs: 17573900, 27256595, 30447144, internal lab contributors). In summary, c.46-2A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting, PP4_Moderate, PP1_Strong, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367403894/MONDO:0015967/086

Frequency

Genomes: not found (cov: 32)

Consequence

GCK
NM_000162.5 splice_acceptor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 7.89

Publications

1 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

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GCKNM_000162.5 linkc.46-2A>G splice_acceptor_variant, intron_variant Intron 1 of 9 ENST00000403799.8 NP_000153.1 P35557-1Q53Y25
GCKNM_033507.3 linkc.49-2A>G splice_acceptor_variant, intron_variant Intron 1 of 9 NP_277042.1 P35557-2
GCKNM_033508.3 linkc.43-2A>G splice_acceptor_variant, intron_variant Intron 2 of 10 NP_277043.1 P35557-3
GCKNM_001354800.1 linkc.46-2A>G splice_acceptor_variant, intron_variant Intron 1 of 10 NP_001341729.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GCKENST00000403799.8 linkc.46-2A>G splice_acceptor_variant, intron_variant Intron 1 of 9 1 NM_000162.5 ENSP00000384247.3 P35557-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Monogenic diabetes Pathogenic:1
Jan 03, 2025
ClinGen Monogenic Diabetes Variant Curation Expert Panel
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation

The c.46-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 1 of NM_000162.5. This variant is predicted to cause an in-frame deletion of part of biologically-relevant exon 2 of 10, a region important for protein function (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMIDs: 17573900, 27256595, 30447144; internal lab contributors). Furthermore, at least three of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 27256595, 30447144; internal lab contributors). This variant segregated with hyperglycemia with 5 informative meioses in 5 families (PP1_Strong; PMIDs: 17573900, 27256595, 30447144, internal lab contributors). In summary, c.46-2A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting, PP4_Moderate, PP1_Strong, PS4. -

Maturity onset diabetes mellitus in young Pathogenic:1
-
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1554335966 in MODY, yet. -

not provided Pathogenic:1
Jan 09, 2017
Athena Diagnostics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
PhyloP100
7.9
GERP RS
5.3
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.62
Position offset: -11
DS_AL_spliceai
0.99
Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1554335966; hg19: chr7-44193064; API