rs754479025

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_000162.5(GCK):c.187C>T(p.Arg63Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain risk allele (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R63H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:1O:1

Conservation

PhyloP100: 3.33

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000162.5

BP4

Computational evidence support a benign effect (MetaRNN=0.41214842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GCK	NM_000162.5 linkuse as main transcript	c.187C>T	p.Arg63Cys	missense_variant	2/10	ENST00000403799.8
GCK	NM_033507.3 linkuse as main transcript	c.190C>T	p.Arg64Cys	missense_variant	2/10
GCK	NM_033508.3 linkuse as main transcript	c.184C>T	p.Arg62Cys	missense_variant	3/11
GCK	NM_001354800.1 linkuse as main transcript	c.187C>T	p.Arg63Cys	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8 linkuse as main transcript	c.187C>T	p.Arg63Cys	missense_variant	2/10	1	NM_000162.5	P1	P35557-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251266

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135820

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727182

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:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance/Uncertain risk allele

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 03, 2017

- -

Maturity onset diabetes mellitus in young

Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs754479025 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Uncertain

-0.040

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Benign

-0.0064

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

D;D;.;D;D

M_CAP

Benign

0.062

MetaRNN

Benign

0.41

T;T;T;T;T

MetaSVM

Pathogenic

0.89

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.68

Sift4G

Benign

0.16

T;T;T;T;T

Polyphen

0.034

B;B;B;B;.

Vest4

0.43

MVP

0.93

MPC

1.4

ClinPred

0.57

GERP RS

5.1

Varity_R

0.59

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over