rs864321656

chr7-44145720-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000162.5(GCK):c.1030G>T(p.Asp344Tyr) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 7.82

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• PP5: Variant 7-44145720-C-A is Pathogenic according to our data. Variant chr7-44145720-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219179.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.1030G>T	p.Asp344Tyr	missense_variant	9/10	ENST00000403799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.1030G>T	p.Asp344Tyr	missense_variant	9/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438394 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 715202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Strand Center for Genomics and Personalized Medicine, Strand Life Sciences Pvt Ltd	-	This is a novel variant present in hexokinase type-2 domain and the amino acid is conserved across mammals, primates and vertebrates. A number of genetic alterations have been reported in association with MODY and diabetes in the vicinity of the observed variant. One such variant, p.Ser340Gly was reported as likely disease causing in association with MODY [ClinVar] Another missense change, p.Ile348Asn was reported in white Caucasians of Slavic origin affected with GCK-MODY. The phenotypes seen in affected population include mild diabetes and/or fasting hyperglycaemia, positive C-peptide at diagnosis and dominant mode of inheritance [PMID:21348868]]. Another variant, p. Glu339Gly was reported to cause MODY [PMID:19790256] as well as hyperglycemia. Functional characterization of this variant showed lower enzyme activity and impaired protein stability. It also impaired the structural conformation of the protein [PMID:21420961]. -
Uncertain significance, criteria provided, single submitter	research	Institute of Endocrinology, Diabetes & Metabolism, Max Healthcare Institute Ltd.	Jun 25, 2017	Uncertain significance -

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 28, 2024

The c.1030G>T variant in the glucokinase gene, GCK, causes an amino acid change of aspartate to tyrosine at codon 344 (p.(Asp344Tyr)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.861, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 27016322, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT 2H increment < 3 mmol/L and negative antibodies) (PP4_Moderate; PMID: 27016322). This variant has been detected in the homozygous state in 1 individual with permanent neonatal diabetes (PM3_Supporting; internal lab contributors). This variant segregated with hyperglycemia with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 27016322). In summary, c.1165G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM2_supporting, PP2, PP3, PM3_Supporting. -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely pathogenic, 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 rs864321656 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
Sift4G	Uncertain	0.049	D;T;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.88
MutPred		0.56		.;.;Gain of loop (P = 0.0195);.;.;.;
MVP		0.95
MPC		2.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.89
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs864321656; hg19: chr7-44185319;