NM_000162.5:c.364C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_SupportingPP2PP3PS4_ModeratePP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.364C>T variant in the glucokinase gene, GCK, causes an amino acid change of leucine to phenylalanine at codon 122 (p.(Leu122Phe)) of NM_000162.5. 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.954, 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 hyperglycemia (PS4_Moderate; PMIDs: 29927023, 31905448, internal lab contributors). However, PP4 is unable to be evaluated due to insufficient clinical information. This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 3 families (PP1_Strong; PMID:31905448, internal lab contributors). In summary, c.364C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP1_Strong, PS4_Moderate, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367402230/MONDO:0015967/086

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense, splice_region

Scores

14

4

1

Splicing: ADA: 0.9955

2

Clinical Significance

Likely pathogenic reviewed by expert panel P:1

Conservation

PhyloP100: 5.88

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5 link	c.364C>T	p.Leu122Phe	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000403799.8	NP_000153.1	P35557-1Q53Y25
GCK	NM_033507.3 link	c.367C>T	p.Leu123Phe	missense_variant, splice_region_variant	Exon 4 of 10		NP_277042.1	P35557-2
GCK	NM_033508.3 link	c.361C>T	p.Leu121Phe	missense_variant, splice_region_variant	Exon 5 of 11		NP_277043.1	P35557-3
GCK	NM_001354800.1 link	c.364C>T	p.Leu122Phe	missense_variant, splice_region_variant	Exon 4 of 11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8 link	c.364C>T	p.Leu122Phe	missense_variant, splice_region_variant	Exon 4 of 10	1	NM_000162.5	ENSP00000384247.3		P35557-1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461602

Hom.:

0

Cov.:

32

AF XY:

0.00000138

AC XY:

1

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

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.:

32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Monogenic diabetes

Pathogenic:1

Aug 01, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.364C>T variant in the glucokinase gene, GCK, causes an amino acid change of leucine to phenylalanine at codon 122 (p.(Leu122Phe)) of NM_000162.5. 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.954, 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 hyperglycemia (PS4_Moderate; PMIDs: 29927023, 31905448, internal lab contributors). However, PP4 is unable to be evaluated due to insufficient clinical information. This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 3 families (PP1_Strong; PMID: 31905448, internal lab contributors). In summary, c.364C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP1_Strong, PS4_Moderate, PP2, PP3, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.52

D

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

32

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;D;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.97

D

LIST_S2

Uncertain

0.95

D;D;.;D

M_CAP

Pathogenic

0.77

D

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.5

.;M;.;.

PrimateAI

Pathogenic

0.89

D

PROVEAN

Uncertain

-3.9

.;D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.89

MutPred

0.95

.;Loss of stability (P = 0.1654);.;.;

MVP

0.98

MPC

2.3

ClinPred

1.0

D

GERP RS

5.0

Varity_R

0.87

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-44190674;