chr7-44153411-A-C

Position:

• chr7-44153411-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The ENST00000403799.8(GCK):​c.98T>G​(p.Val33Gly) 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 risk allele (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V33A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK ENST00000403799.8 missense
• Clinical Significance: Likely risk allele criteria provided, single submitter P: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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000403799.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-44153411-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 585930.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 7-44153411-A-C is Pathogenic according to our data. Variant chr7-44153411-A-C is described in ClinVar as [Likely_risk_allele]. Clinvar id is 1801853.Status of the report is criteria_provided_single_submitter, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_risk_allele=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.98T>G	p.Val33Gly	missense_variant	2/10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.101T>G	p.Val34Gly	missense_variant	2/10		NP_277042.1
GCK	NM_033508.3	c.95T>G	p.Val32Gly	missense_variant	3/11		NP_277043.1
GCK	NM_001354800.1	c.98T>G	p.Val33Gly	missense_variant	2/11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.98T>G	p.Val33Gly	missense_variant	2/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely risk allele

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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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 rs1554335954 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;.;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.7	.;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.68
MutPred		0.78		.;Loss of stability (P = 0.0146);.;.;Loss of stability (P = 0.0146);
MVP		1.0
MPC		2.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554335954; hg19: chr7-44193010;