chr7-44153475-G-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000162.5(GCK):c.46-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,613,358 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000162.5 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.46-12C>T | intron_variant | Intron 1 of 9 | ENST00000403799.8 | NP_000153.1 | ||
GCK | NM_033507.3 | c.49-12C>T | intron_variant | Intron 1 of 9 | NP_277042.1 | |||
GCK | NM_033508.3 | c.43-12C>T | intron_variant | Intron 2 of 10 | NP_277043.1 | |||
GCK | NM_001354800.1 | c.46-12C>T | intron_variant | Intron 1 of 10 | NP_001341729.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00279 AC: 424AN: 152176Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00375 AC: 939AN: 250260Hom.: 4 AF XY: 0.00380 AC XY: 514AN XY: 135320
GnomAD4 exome AF: 0.00318 AC: 4651AN: 1461064Hom.: 13 Cov.: 37 AF XY: 0.00319 AC XY: 2318AN XY: 726854
GnomAD4 genome AF: 0.00278 AC: 424AN: 152294Hom.: 4 Cov.: 32 AF XY: 0.00322 AC XY: 240AN XY: 74462
ClinVar
Submissions by phenotype
not provided Benign:4
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not specified Benign:3
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Variant summary: GCK c.46-12C>T alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools (TraP) predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0038 in 250260 control chromosomes, predominantly at a frequency of 0.0051 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 204-fold of the estimated maximal expected allele frequency for a pathogenic variant in GCK causing maturity-onset diabetes of the young type 2 phenotype (2.5e-05). c.46-12C>T has been reported in the literature (PMID: 8454109, 8433729, 8068341). These report(s) do not provide unequivocal conclusions about association of the variant with maturity-onset diabetes of the young type 2. The following publications have been ascertained in the context of this evaluation (PMID: 8454109, 8433729, 8068341, 7555485, 16963153, 18271687). ClinVar contains an entry for this variant (Variation ID: 36222). Based on the evidence outlined above, the variant was classified as benign. -
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Maturity onset diabetes mellitus in young Benign:2
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 rs142829768 in MODY, yet. -
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Transient Neonatal Diabetes, Recessive Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Maturity-onset diabetes of the young type 2 Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Permanent neonatal diabetes mellitus Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Hyperinsulinism due to glucokinase deficiency Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at