7-44145630-C-T

Variant names:

• chr7-44145630-C-T
• rs1415041911
• NM_000162.5:c.1120G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP4_Moderate PM2_Supporting PP2 PP3 PS4_Moderate PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1120G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 374 (p.(Val374Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; Zubkova et al. World Journal of Personalized Medicine. 2017;1(1):40-48, internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367398877/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCK NM_001354802.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 7.83

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.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.1120G>A	p.Val374Met	missense_variant	Exon 9 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1120G>A	p.Val374Met	missense_variant	Exon 9 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454376 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723574

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Nov 03, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1120G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 374 (p.(Val374Met)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; Zubkova et al. World Journal of Personalized Medicine. 2017;1(1):40-48, internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PS4_Moderate, PP1_Moderate, PP4_Moderate. -

not specified Uncertain:1

Aug 26, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;D;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;.;M;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.9	.;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.023	.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.97
MutPred		0.96		.;.;Gain of disorder (P = 0.0423);.;.;.;
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.99

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: rs1415041911; hg19: chr7-44185229;