rs193922325

Positions:

• chr7-44153435-A-C
• chr7-44153435-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000162.5(GCK):​c.74T>G​(p.Leu25Arg) 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]

GCK (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 7-44153435-A-C is Pathogenic according to our data. Variant chr7-44153435-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36250.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_risk_allele=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.74T>G	p.Leu25Arg	missense_variant	2/10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.77T>G	p.Leu26Arg	missense_variant	2/10		NP_277042.1
GCK	NM_033508.3	c.71T>G	p.Leu24Arg	missense_variant	3/11		NP_277043.1
GCK	NM_001354800.1	c.74T>G	p.Leu25Arg	missense_variant	2/11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.74T>G	p.Leu25Arg	missense_variant	2/10	1	NM_000162.5	ENSP00000384247.3

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:1

Likely pathogenic, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely risk allele, 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 rs193922325 in MODY, yet. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2023

ClinVar contains an entry for this variant (Variation ID: 36250). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 25 of the GCK protein (p.Leu25Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GCK-related conditions. 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	0.73
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;.;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;H;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.3	.;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.93
MutPred		0.54		.;Gain of MoRF binding (P = 0.0067);.;.;Gain of MoRF binding (P = 0.0067);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs193922325; hg19: chr7-44193034;