7-44149975-CCG-TCC

Variant names:

• chr7-44149975-CCG-TCC
• NM_000162.5:c.571_573delCGGinsGGA
• GCK p.Arg191Gly

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5

The NM_000162.5(GCK):c.571_573delCGGinsGGA (p.Arg191Gly) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R191Q: Pathogenic (ClinVar VariationId 283358, 3 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R191G: Uncertain_significance (ClinVar VariationId 804850, 1 star); p.R191L: Uncertain_significance (ClinVar VariationId 4747570, 1 star); p.R191= (synonymous): Likely_benign (ClinVar VariationId 4761929, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• 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):

• hyperinsulinemic hypoglycemia, familial, 3

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

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

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• type 2 diabetes mellitus

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

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

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 15 pathogenic, 0 benign (OR vs. background: 155.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R191Q: Pathogenic (ClinVar VariationId 283358, 3 stars); Other variants at the same amino acid residue (not pathogenic): p.R191G: Uncertain_significance (ClinVar VariationId 804850, 1 star); p.R191L: Uncertain_significance (ClinVar VariationId 4747570, 1 star); p.R191= (synonymous): Likely_benign (ClinVar VariationId 4761929, 1 star)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GCK NM_000162.5	MANE Select	c.571_573delCGGinsGGA p.Arg191Gly	missense	N/A	Prot: NP_000153.1 UniProt:
	GCK NM_033507.3		c.574_576delCGGinsGGA p.Arg192Gly	missense	N/A	Prot: NP_277042.1 UniProt:
	GCK NM_033508.3		c.568_570delCGGinsGGA p.Arg190Gly	missense	N/A	Prot: NP_277043.1 UniProt:

GCK NM_000162.5

MANE Select

HGVSc / HGVSpc.571_573delCGGinsGGAp.Arg191Gly

Exon rankN/A

missense

Prot: NP_000153.1UniProt: P35557-1Q53Y25

GCK NM_033507.3

HGVSc / HGVSpc.574_576delCGGinsGGAp.Arg192Gly

Exon rankN/A

missense

Prot: NP_277042.1UniProt: P35557-2

GCK NM_033508.3

HGVSc / HGVSpc.568_570delCGGinsGGAp.Arg190Gly

Exon rankN/A

missense

Prot: NP_277043.1UniProt: P35557-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GCK ENST00000403799.8	TSL:1MANE Select	c.571_573delCGGinsGGA p.Arg191Gly	missense	N/A	Prot: ENSP00000384247.3 UniProt:
	GCK ENST00000395796.8	TSL:1	n.*569_*571delCGGinsGGA	3_prime_UTR	Exon 6 of 11	Prot: ENSP00000379142.4 UniProt:
	GCK ENST00000395796.8	TSL:1	n.*569_*571delCGGinsGGA	non_coding_transcript_exon	Exon 6 of 11	Prot: ENSP00000379142.4 UniProt:

GCK ENST00000403799.8

TSL:1MANE Select

HGVSc / HGVSpc.571_573delCGGinsGGAp.Arg191Gly

Exon rankN/A

missense

Prot: ENSP00000384247.3UniProt: P35557-1

GCK ENST00000395796.8

TSL:1

HGVSc / HGVSpn.*569_*571delCGGinsGGA

Exon rankExon 6 of 11

3_prime_UTR

Prot: ENSP00000379142.4UniProt: A0A8C8KJG0

GCK ENST00000395796.8

TSL:1

HGVSc / HGVSpn.*569_*571delCGGinsGGA

Exon rankExon 6 of 11

non_coding_transcript_exon

Prot: ENSP00000379142.4UniProt: A0A8C8KJG0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	6.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

2 abnormal

1 no calibration

3 assays found for this variant.

Clinical calibration: 2 functionally abnormal (PS3), 0 functionally normal (BS3).

No calibration: 1 assay (score only).

Protein level

GCK variant abundance measured by DHFR-PCA

GCK abundance measured by DHFR-PCA

• Gene: GCK
• Assay type: Reporter
• Mechanism: Loss of function
• Model system: Yeast (Saccharomyces cerevisiae)
• Score: 0.586 · p.Arg191Gly (assay numbering)

Classified as

PS3 Functionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Unclassified

+1 more calibration

PS3 Functionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Unclassified

Protein level

GCK activity measured by complementation

• Gene: GCK
• Assay type: Cell fitness
• Mechanism: Gain or loss of function
• Model system: Yeast (Saccharomyces cerevisiae)
• Score: -0.392 · p.Arg191Gly (assay numbering)

Classified as

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Decreased activity

+2 more calibrations

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Decreased activity

PS3 strongFunctionally abnormalRUO ExCALIBR calibration: PS3 Strong (4)

Protein level

GCK Y2H

• Gene: GCK
• Assay type: Cell proliferation assay
• Model system: Yeast
• Score: 0.688 · p.Arg191Gly (assay numbering)

No calibration data

This score is at approximately the 33th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

hg19: chr7-44189574;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar