GeneBe

7-44153381-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP1_ModeratePM5_SupportingPP2PP3PM2_SupportingPP4_ModeratePS4

This summary comes from the ClinGen Evidence Repository: The c.128G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 43 (p.(Arg43His)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8159, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated that the p.Arg43His variant has normal relative activity index (RAI>0.5) and normal GKA/GKRP interaction; however the relative stability index (RSI) was not calculated and therefore neither PS3 or BS3 can be applied (PMID:22611063). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; PMIDs: 11942313, 22611063, 27106716, 25015100, 22493702, 30245511, 31638168, 33046911). 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 OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:30245511). This variant segregated with diabetes/hyperglycemia, with three informative meioses in two families (PP1_Moderate; PMIDs: 22611063, 22493702). Another missense variant, c.127C>T (p.Arg43Cys), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg43His (PM5_Supporting). In summary, the c.128G>A variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified for by the GlinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PP1_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA4239718/MONDO:0015967/086

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

9
7
3

Clinical Significance

Pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 4.14

Publications

15 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, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000162.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GCK
NM_000162.5
MANE Select
c.128G>Ap.Arg43His
missense
Exon 2 of 10NP_000153.1Q53Y25
GCK
NM_033507.3
c.131G>Ap.Arg44His
missense
Exon 2 of 10NP_277042.1P35557-2
GCK
NM_033508.3
c.125G>Ap.Arg42His
missense
Exon 3 of 11NP_277043.1P35557-3

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GCK
ENST00000403799.8
TSL:1 MANE Select
c.128G>Ap.Arg43His
missense
Exon 2 of 10ENSP00000384247.3P35557-1
GCK
ENST00000395796.8
TSL:1
n.*126G>A
non_coding_transcript_exon
Exon 3 of 11ENSP00000379142.4A0A8C8KJG0
GCK
ENST00000395796.8
TSL:1
n.*126G>A
3_prime_UTR
Exon 3 of 11ENSP00000379142.4A0A8C8KJG0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251444
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461864
Hom.:
0
Cov.:
34
AF XY:
0.00000413
AC XY:
3
AN XY:
727226
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53396
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112010
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
4
-
-
Monogenic diabetes (4)
3
-
-
not provided (3)
2
-
-
Maturity-onset diabetes of the young (2)
1
-
-
GCK-related disorder (1)
1
-
-
Maturity-onset diabetes of the young type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.87
D
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.77
T
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.1
M
PhyloP100
4.1
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-2.8
D
REVEL
Pathogenic
0.82
Sift
Benign
0.034
D
Sift4G
Uncertain
0.056
T
Varity_R
0.79
gMVP
0.92
Mutation Taster
=3/97
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

Other links and lift over

dbSNP: rs764232985;
hg19: chr7-44192980;
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