rs1131691505

Variant names:

• chr7-44145611-TGCGCAGCGC-T
• rs1131691505
• NM_000162.5:c.1130_1138delGCGCTGCGC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1130_1138del variant in the glucokinase gene, GCK, is a 9 base pair deletion resulting in the in-frame deletion of 3 amino acids at codon 377 (p.(Arg377_Ala379del)) within exon 9 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.1130_1138del variant is predicted to change the length of the protein due an in-frame deletion of three amino acids in a non-repeat region (PM4). This variant segregated with hyperglycemia with two informative meioses in one family with MODY, which is below the threshold for PP1 (PMID:31063852). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMID 31063852, internal lab contributors). This variant was identified in an individual with hyperglycemia, however, PP4 is unable to be evaluated due to insufficient clinical information. In summary, this variant meets the criteria to be classified as uncertain significance for monogenic diabetes, ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA645369436/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_033507.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 8.06
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033507.3. 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.1130_1138delGCGCTGCGC	p.Arg377_Ala379del	disruptive_inframe_deletion	Exon 9 of 10	NP_000153.1
	GCK	NM_033507.3		c.1133_1141delGCGCTGCGC	p.Arg378_Ala380del	disruptive_inframe_deletion	Exon 9 of 10	NP_277042.1
	GCK	NM_033508.3		c.1127_1135delGCGCTGCGC	p.Arg376_Ala378del	disruptive_inframe_deletion	Exon 10 of 11	NP_277043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.1130_1138delGCGCTGCGC	p.Arg377_Ala379del	disruptive_inframe_deletion	Exon 9 of 10	ENSP00000384247.3
	GCK	ENST00000395796.8	TSL:1	n.*1128_*1136delGCGCTGCGC		non_coding_transcript_exon	Exon 10 of 11	ENSP00000379142.4
	GCK	ENST00000459642.1	TSL:1	n.510_518delGCGCTGCGC		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Maturity onset diabetes mellitus in young (1)
-	1	-	Monogenic diabetes (1)
1	-	-	not provided (1)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1131691505; hg19: chr7-44185210;