7-44150961-C-T

Position:

• chr7-44150961-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000162.5(GCK):​c.478G>A​(p.Asp160Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 O:1
• Conservation: PhyloP100: 4.98

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 7 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: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 7-44150961-C-T is Pathogenic according to our data. Variant chr7-44150961-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447404.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_risk_allele=1, Uncertain_significance=2, Pathogenic=1}. Variant chr7-44150961-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.478G>A	p.Asp160Asn	missense_variant	4/10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.481G>A	p.Asp161Asn	missense_variant	4/10		NP_277042.1
GCK	NM_033508.3	c.475G>A	p.Asp159Asn	missense_variant	5/11		NP_277043.1
GCK	NM_001354800.1	c.478G>A	p.Asp160Asn	missense_variant	4/11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.478G>A	p.Asp160Asn	missense_variant	4/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461638 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 160 of the GCK protein (p.Asp160Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 19790256, 25015100, 32533152, 33852230, 36257325). ClinVar contains an entry for this variant (Variation ID: 447404). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 25015100). This variant disrupts the p.Asp160 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29056535, 30608898). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

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

Pathogenic, criteria provided, single submitter

research

Geisinger Clinic, Geisinger Health System

Aug 02, 2022

PM2, PP1_Strong, PS4, PM5_Supporting, PP4, PP2, PS3 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 22, 2024

Variant summary: GCK c.478G>A (p.Asp160Asn) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251458 control chromosomes (gnomAD). c.478G>A has been reported in the literature in individuals affected with maturity-onset diabetes of the young as well as in two carriers in non-diabetes (Osbak_2009, Raimondo_2014, Caswell_2020, Breidbart_2021, Mirshahi_2022, Billings_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Raimondo_2014). The following publications have been ascertained in the context of this evaluation (PMID: 36208030, 33852230, 32533152, 36257325, 19790256, 25015100). ClinVar contains an entry for this variant (Variation ID: 447404). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Maturity onset diabetes mellitus in young Other:1

Uncertain 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 rs1554335566 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	.;D;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.71	.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.6	.;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.034	.;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		1.0	D;D;D;B;.
Vest4		0.91
MutPred		0.83		.;Loss of stability (P = 0.0639);.;.;.;
MVP		0.94
MPC		2.0
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.66
gMVP		0.90

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: rs1554335566; hg19: chr7-44190560; COSMIC: COSV60786479; COSMIC: COSV60786479;