rs1554335751

chr7-44152339-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000162.5(GCK):c.295T>C(p.Trp99Arg) variant causes a missense change. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W99C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.27

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 4 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 7-44152339-A-G is Pathogenic according to our data. Variant chr7-44152339-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447394.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.295T>C	p.Trp99Arg	missense_variant	3/10	ENST00000403799.8
GCK	NM_033507.3	c.298T>C	p.Trp100Arg	missense_variant	3/10
GCK	NM_033508.3	c.292T>C	p.Trp98Arg	missense_variant	4/11
GCK	NM_001354800.1	c.295T>C	p.Trp99Arg	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.295T>C	p.Trp99Arg	missense_variant	3/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2017	The W99R variant in the GCK gene has been reported previously in a family with familial hypoglycemia (Gloyn et al., 2003). The W99R variant is not observed in large population cohorts (Lek et al., 2016). The W99R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies of W99R indicate that it leads to enhanced glucose binding (Gloyn et al., 2003; Heredia et al., 2006). We interpret W99R as a pathogenic variant. -

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

Uncertain significance, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	24
Dann	Benign	0.96
Eigen	Benign	0.13
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.65	T;T;.;T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
Sift4G	Benign	0.35	T;T;T;T;T
Polyphen		1.0	D;D;D;B;.
Vest4		0.88
MutPred		0.82		.;Gain of disorder (P = 0.0184);.;.;Gain of disorder (P = 0.0184);
MVP		0.99
MPC		2.8
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.77
gMVP		0.99

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: rs1554335751; hg19: chr7-44191938;