rs191255582
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000162.5(GCK):c.364-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,613,440 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 2 hom. )
Consequence
GCK
NM_000162.5 intron
NM_000162.5 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.55
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
Variant 7-44151093-T-C is Benign according to our data. Variant chr7-44151093-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 514377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44151093-T-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00113 (172/152316) while in subpopulation AFR AF= 0.00344 (143/41574). AF 95% confidence interval is 0.00298. There are 0 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.364-18A>G | intron_variant | ENST00000403799.8 | |||
GCK | NM_001354800.1 | c.364-18A>G | intron_variant | ||||
GCK | NM_033507.3 | c.367-18A>G | intron_variant | ||||
GCK | NM_033508.3 | c.361-18A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.364-18A>G | intron_variant | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00114 AC: 173AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000311 AC: 78AN: 250628Hom.: 1 AF XY: 0.000265 AC XY: 36AN XY: 135628
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GnomAD4 exome AF: 0.000141 AC: 206AN: 1461124Hom.: 2 Cov.: 32 AF XY: 0.000122 AC XY: 89AN XY: 726832
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GnomAD4 genome AF: 0.00113 AC: 172AN: 152316Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78AN XY: 74484
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 12, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Maturity onset diabetes mellitus in young Benign:1
Benign, 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 . However, there is no sufficient evidence to ascertain the significance of rs191255582 in MODY, yet. - |
Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinism due to glucokinase deficiency;C5393570:Permanent neonatal diabetes mellitus 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 30, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at