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

Genomes: 𝑓 0.0028 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 13 hom. )

Consequence

GCK
NM_000162.5 intron

Scores

2
Splicing: ADA: 0.00001948
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.362
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]

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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=-0.85).
BP6
Variant 7-44153475-G-A is Benign according to our data. Variant chr7-44153475-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44153475-G-A is described in Lovd as [Likely_benign]. Variant chr7-44153475-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00278 (424/152294) while in subpopulation NFE AF= 0.00344 (234/68024). AF 95% confidence interval is 0.00308. There are 4 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GCKNM_000162.5 linkc.46-12C>T intron_variant Intron 1 of 9 ENST00000403799.8 NP_000153.1 P35557-1Q53Y25
GCKNM_033507.3 linkc.49-12C>T intron_variant Intron 1 of 9 NP_277042.1 P35557-2
GCKNM_033508.3 linkc.43-12C>T intron_variant Intron 2 of 10 NP_277043.1 P35557-3
GCKNM_001354800.1 linkc.46-12C>T 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.46-12C>T intron_variant Intron 1 of 9 1 NM_000162.5 ENSP00000384247.3 P35557-1

Frequencies

GnomAD3 genomes
AF:
0.00279
AC:
424
AN:
152176
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.0158
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00344
Gnomad OTH
AF:
0.000958
GnomAD3 exomes
AF:
0.00375
AC:
939
AN:
250260
Hom.:
4
AF XY:
0.00380
AC XY:
514
AN XY:
135320
show subpopulations
Gnomad AFR exome
AF:
0.000370
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.000797
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.0151
Gnomad NFE exome
AF:
0.00508
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00318
AC:
4651
AN:
1461064
Hom.:
13
Cov.:
37
AF XY:
0.00319
AC XY:
2318
AN XY:
726854
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000301
Gnomad4 FIN exome
AF:
0.0160
Gnomad4 NFE exome
AF:
0.00323
Gnomad4 OTH exome
AF:
0.00253
GnomAD4 genome
AF:
0.00278
AC:
424
AN:
152294
Hom.:
4
Cov.:
32
AF XY:
0.00322
AC XY:
240
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.000337
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.0158
Gnomad4 NFE
AF:
0.00344
Gnomad4 OTH
AF:
0.000948
Alfa
AF:
0.00301
Hom.:
0
Bravo
AF:
0.00163

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 20, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 05, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 27, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:3
Jul 29, 2015
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 08, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Benign:2
-
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance: Benign
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 rs142829768 in MODY, yet. -

Feb 11, 2015
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
8.6
DANN
Benign
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000019
dbscSNV1_RF
Benign
0.010
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142829768; hg19: chr7-44193074; API