rs876661320

chr7-44153420-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000162.5(GCK):c.89T>C(p.Leu30Pro) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.29

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000162.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 7-44153420-A-G is Pathogenic according to our data. Variant chr7-44153420-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235097.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.89T>C	p.Leu30Pro	missense_variant	2/10	ENST00000403799.8
GCK	NM_033507.3	c.92T>C	p.Leu31Pro	missense_variant	2/10
GCK	NM_033508.3	c.86T>C	p.Leu29Pro	missense_variant	3/11
GCK	NM_001354800.1	c.89T>C	p.Leu30Pro	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.89T>C	p.Leu30Pro	missense_variant	2/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Kangwon National University Hospital	Jul 17, 2017	Glucokinase-maturityonset diabetes of the young (GCKMODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. Because people with GCK-MODY do not develop significant microvascular complications, treatment is not recommended except pregnancy. Glucose-lowering therapy is ineffective in people with GCK-MODY. -
Likely pathogenic, criteria provided, single submitter	clinical testing	National Newborn Screening Laboratory, Hospital Nacional de Niños	-	This is a missense variant located within exon 2 and generates a change from the amino acid Leucine to Proline in position 30. It is a non-synonymous varian located in a mutational hot-spot (PM1). It is a missense variant in a gene with low rate of missense variation for which missense variants are a common mechanism of a disease(PP2). It is not present in population databases (GnomAD exomes, GnomAD genomes) (PM2). Multiple lines of computational evidence support a deleterious effect on the gene (PP3). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 30 of the GCK protein (p.Leu30Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 19564454, 28555465). ClinVar contains an entry for this variant (Variation ID: 235097). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCK protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;.;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.98
MutPred		0.92		.;Gain of loop (P = 0.0051);.;.;Gain of loop (P = 0.0051);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
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: rs876661320; hg19: chr7-44193019;