chr7-44147834-C-T

Variant names:

• chr7-44147834-C-T
• rs1057524905
• NM_000162.5:c.680-1G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000162.5(GCK):​c.680-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.86

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]

LOC105375258 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.4, offset of 1, new splice context is: cccccgacctccaccccaAGcac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-44147834-C-T is Pathogenic according to our data. Variant chr7-44147834-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 393452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.680-1G>A		splice_acceptor_variant, intron_variant	Intron 6 of 9	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.680-1G>A		splice_acceptor_variant, intron_variant	Intron 6 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Pathogenic:1

Feb 09, 2017

Translational Genomics Laboratory, University of Maryland School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.680-1G>A variant in the GCK gene removes a splice acceptor site in IVS6 (19339519). Canonical splice site variants can often be assumed to disrupt gene function by leading to a complete absence of the gene product by lack of transcription or nonsense-mediated decay of an altered transcript. The c.680-1G>A variant has previously been reported (16965331) in a patient with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY), as have other splice site mutations in the GCK gene (19790256, 14517946). The c.680-1G>A variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases. Multiple lines of computational evidence (MutationTaster, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PVS1, PM2, PP3 -

Maturity onset diabetes mellitus in young Pathogenic:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely pathogenic

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 rs1057524905 in MODY, yet. -

Monogenic diabetes Pathogenic:1

Apr 22, 2016

Translational Genomics Laboratory, University of Maryland School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.680-1G>A variant in the GCK gene removes a splice acceptor site in IVS6 (19339519). Canonical splice site variants can often be assumed to disrupt gene function by leading to a complete absence of the gene product by lack of transcription or nonsense-mediated decay of an altered transcript. The c.680-1G>A variant has previously been reported (16965331) in a patient with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY), as have other splice site mutations in the GCK gene (19790256, 14517946). The c.680-1G>A variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases. Multiple lines of computational evidence (MutationTaster, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PVS1, PM2, PP3 -

not provided Pathogenic:1

Oct 22, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.97	D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: -2
DS_AL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057524905; hg19: chr7-44187433;