NM_000162.5:c.483G>C

Variant names:

• chr7-44150956-C-G
• NM_000162.5:c.483G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000162.5(GCK):​c.483G>C​(p.Lys161Asn) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK NM_000162.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84

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 8 ACMG points.

• PM1: In a region_of_interest Hexokinase small subdomain (size 136) in uniprot entity HXK4_HUMAN there are 46 pathogenic changes around while only 2 benign (96%) in NM_000162.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.483G>C	p.Lys161Asn	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.486G>C	p.Lys162Asn	missense_variant, splice_region_variant	Exon 4 of 10		NP_277042.1
GCK	NM_033508.3	c.480G>C	p.Lys160Asn	missense_variant, splice_region_variant	Exon 5 of 11		NP_277043.1
GCK	NM_001354800.1	c.483G>C	p.Lys161Asn	missense_variant, splice_region_variant	Exon 4 of 11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.483G>C	p.Lys161Asn	missense_variant, splice_region_variant	Exon 4 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	37
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;D;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;D;.;T;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	.;L;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.8	.;N;N;N;N
REVEL	Pathogenic	0.76
Sift	Benign	0.072	.;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		1.0	D;D;D;P;.
Vest4		0.90
MutPred		0.80		.;Loss of ubiquitination at K161 (P = 0.0161);.;.;.;
MVP		0.96
MPC		2.4
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.80
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.83		Position offset: 24
DS_DL_spliceai		0.61		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-44190555;