rs1554334433
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP3
The NM_000162.5(GCK):c.1363_1364insCGG(p.Ala454dup) variant causes a inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
GCK
NM_000162.5 inframe_insertion
NM_000162.5 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.70
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000162.5
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-44145170-A-ACCG is Pathogenic according to our data. Variant chr7-44145170-A-ACCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435297.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
BP3
?
Nonframeshift variant in repetitive region in NM_000162.5
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.1363_1364insCGG | p.Ala454dup | inframe_insertion | 10/10 | ENST00000403799.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.1363_1364insCGG | p.Ala454dup | inframe_insertion | 10/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hyperinsulinism due to glucokinase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 27, 2016 | - - |
Maturity onset diabetes mellitus in young Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | 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 well. However, there is no sufficient evidence to assertain the significance of rs1554334433 in MODY, yet. This variant is shown to be potentially damaging by insilico analysis. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at