chr7-44146531-G-T

Variant names:

• chr7-44146531-G-T
• rs1379908545
• NM_000162.5:c.951C>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 15P and 1B. PS1_Very_Strong PM1 PM2 PP2 PP5_Moderate BP4

The NM_000162.5(GCK):​c.951C>A​(p.His317Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H317P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.348
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinism due to glucokinase deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300758 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_000162.5 (GCK) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 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
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 274 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.069 (below the threshold of 3.09). Trascript score misZ: 2.7821 (below the threshold of 3.09). GenCC associations: The gene is linked to transient neonatal diabetes mellitus, monogenic diabetes, permanent neonatal diabetes mellitus 1, diabetes mellitus, noninsulin-dependent, maturity-onset diabetes of the young type 2, hyperinsulinism due to glucokinase deficiency, permanent neonatal diabetes mellitus, maturity-onset diabetes of the young.
• PP5: Variant 7-44146531-G-T is Pathogenic according to our data. Variant chr7-44146531-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2861776.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18545276). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.951C>A	p.His317Gln	missense_variant	Exon 8 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.951C>A	p.His317Gln	missense_variant	Exon 8 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 317 of the GCK protein (p.His317Gln). This variant is not present in population databases (gnomAD no frequency). A different variant (c.951C>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 31063852; Invitae). This suggests that this variant is also likely to be causative of disease. 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 not expected to disrupt GCK protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.66
DEOGEN2	Benign	0.37	.;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.70	T;T;.;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	-1.3	.;N;.;.;.
PhyloP100		-0.35
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.54	.;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.25	.;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T
Polyphen		0.010	B;B;B;B;.
Vest4		0.15
MutPred		0.41		.;Gain of disorder (P = 0.1464);.;.;.;
MVP		0.75
MPC		1.1
ClinPred		0.18	T
GERP RS		2.9
PromoterAI		-0.018	Neutral
Varity_R		0.22
gMVP		0.78
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1379908545; hg19: chr7-44186130;