rs1085307455

Variant names:

• chr7-44149977-G-A
• rs1085307455
• NM_000162.5:c.571C>T
• GCK p.Arg191Trp

Your query was ambiguous. Multiple possible variants found:

• chr7-44149977-G-A
• chr7-44149977-G-C
• chr7-44149977-G-T

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 22 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000162.5(GCK):c.571C>T (p.Arg191Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000109 (AC=16) in the gnomAD database across 1,461,634 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000575. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000576488: Published functional studies demonstrate a damaging effect on protein activity and stability (Wang et al., 2019);" and additional evidence is available in 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) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 0.949
• Publications: 33 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: Pathogenic. The variant received 22 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000576488: Published functional studies demonstrate a damaging effect on protein activity and stability (Wang et al., 2019);; SCV000613442: Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant results in reduced enzyme activity compared to the wild type (PMID: 30592380).; SCV005185836: "In addition, at least one publication reported experimental evidence evaluating an impact on protein function, demonstrating that the variant resulted in reduced enzyme activity compared to the wild type (Wang_2019)."
	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		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000575 — very rare for AD+AR gene (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)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (14/14 total P/LP).

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.571C>T p.Arg191Trp	missense	Exon 5 of 10	Prot: NP_000153.1 UniProt:
	GCK NM_033507.3		c.574C>T p.Arg192Trp	missense	Exon 5 of 10	Prot: NP_277042.1 UniProt:
	GCK NM_033508.3		c.568C>T p.Arg190Trp	missense	Exon 6 of 11	Prot: NP_277043.1 UniProt:

GCK NM_000162.5

MANE Select

HGVSc / HGVSpc.571C>Tp.Arg191Trp

Exon rankExon 5 of 10

missense

Prot: NP_000153.1UniProt: P35557-1Q53Y25

GCK NM_033507.3

HGVSc / HGVSpc.574C>Tp.Arg192Trp

Exon rankExon 5 of 10

missense

Prot: NP_277042.1UniProt: P35557-2

GCK NM_033508.3

HGVSc / HGVSpc.568C>Tp.Arg190Trp

Exon rankExon 6 of 11

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.571C>T p.Arg191Trp	missense	Exon 5 of 10	Prot: ENSP00000384247.3 UniProt:
	GCK ENST00000395796.8	TSL:1	n.*569C>T	3_prime_UTR	Exon 6 of 11	Prot: ENSP00000379142.4 UniProt:
	GCK ENST00000395796.8	TSL:1	n.*569C>T	non_coding_transcript_exon	Exon 6 of 11	Prot: ENSP00000379142.4 UniProt:

GCK ENST00000403799.8

TSL:1MANE Select

HGVSc / HGVSpc.571C>Tp.Arg191Trp

Exon rankExon 5 of 10

missense

Prot: ENSP00000384247.3UniProt: P35557-1

GCK ENST00000395796.8

TSL:1

HGVSc / HGVSpn.*569C>T

Exon rankExon 6 of 11

3_prime_UTR

Prot: ENSP00000379142.4UniProt: A0A8C8KJG0

GCK ENST00000395796.8

TSL:1

HGVSc / HGVSpn.*569C>T

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD2 exomes	AF: 0.00000796	AC:2	Hom:	AN:251110	Cov:
GnomAD4 exome	AF: 0.0000109	AC:16	Hom:0	AN:1461634	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16838	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122096	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000115	1	86988	0.00000689	1	145038

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Maturity-onset diabetes of the young type 2 (4)
2	-	-	Maturity-onset diabetes of the young (2)
1	-	-	GCK-related disorder (1)
1	-	-	Monogenic diabetes (1)
1	-	-	Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinemic hypoglycemia, familial, 3;C5393570:Permanent neonatal diabetes mellitus 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.85	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-9.3
GPN-Star score	N/A	8.5
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	4/96	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.6	H
PhyloP100	Benign	0.95
popEVE	Benign	-4.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.98
VESM-3B	Benign	-12

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.060
SpliceAI score (max)	Benign	0.060	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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: 0.262 · p.Arg191Trp (assay numbering)

Classified as

PS3 strongFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Low abundance

+2 more calibrations

PS3 supportingFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Low abundance

PS3 strongFunctionally abnormalRUO ExCALIBR calibration: PS3 Strong (4)

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: 0.0301 · p.Arg191Trp (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 moderateFunctionally abnormalRUO ExCALIBR calibration: PS3 Moderate (2)

Protein level

GCK Y2H

• Gene: GCK
• Assay type: Cell proliferation assay
• Model system: Yeast
• Score: 0.552 · p.Arg191Trp (assay numbering)

No calibration data

This score is at approximately the 23th 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

dbSNP: rs1085307455;

hg19: chr7-44189576;

COSMIC: COSV60785720;

COSMIC: COSV60785720;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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