rs193921338

Variant names:

• chr7-44145590-G-A
• rs193921338
• NM_000162.5:c.1160C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-44145590-G-A
• chr7-44145590-G-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM5 PP2 PP3 PM2_Supporting PP4_Moderate PS4_Moderate PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1160C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 387 (p. (Ala387Val)) of NM_000162.5. This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to no copies in the European non-Finnish subpopulation and one copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is located in the larger hexokinase domain of the GCK gene (PMID:31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein’s function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.871 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1159G>A p.(Ala387Thr) has been interpreted as pathogenic by the ClinGen MDEP, and p.Ala387Glu has a greater Grantham distance (PM5). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID:34421822, Internal lab contributors). One of these individuals had 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; PMID:34421822). This variant segregated with hyperglycemia, with five informative meioses in three families (PP1_Strong; PMID:34421822, Internal lab contributor). In summary, c.1160C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP2, PP3, PM2_Supporting, PP1_Strong, PM5, PS4_Moderate, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213727/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 9.90
• Publications: 14 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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

Specifications for GCK are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 13 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.
• PM5: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000162.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.1160C>T	p.Ala387Val	missense	Exon 9 of 10	NP_000153.1	Q53Y25
	GCK	NM_033507.3		c.1163C>T	p.Ala388Val	missense	Exon 9 of 10	NP_277042.1	P35557-2
	GCK	NM_033508.3		c.1157C>T	p.Ala386Val	missense	Exon 10 of 11	NP_277043.1	P35557-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.1160C>T	p.Ala387Val	missense	Exon 9 of 10	ENSP00000384247.3	P35557-1
	GCK	ENST00000395796.8	TSL:1	n.*1158C>T		non_coding_transcript_exon	Exon 10 of 11	ENSP00000379142.4	A0A8C8KJG0
	GCK	ENST00000459642.1	TSL:1	n.540C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000436 AC: 1 AN: 229466 AF XY: 0.00000795

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452264 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 722294

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 44010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39382

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109296

Other (OTH) AF: 0.00 AC: 0 AN: 60008

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000390 Hom.: 0

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Monogenic diabetes (2)
1	1	-	not provided (2)
1	-	-	Maturity-onset diabetes of the young type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	M
PhyloP100		9.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.87
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.73
MutPred		0.94		Loss of disorder (P = 0.121)
MVP		0.98
MPC		2.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.76
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193921338; hg19: chr7-44185189;