7-44188923-C-T

Position:

chr7-44188923-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000162.5(GCK):c.31G>A(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,882 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 9 hom., cov: 33)

Exomes 𝑓: 0.00067 ( 9 hom. )

Consequence

GCK
NM_000162.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.880

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 Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000162.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0042022765).

BP6

Variant 7-44188923-C-T is Benign according to our data. Variant chr7-44188923-C-T is described in ClinVar as [Benign]. Clinvar id is 129141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44188923-C-T is described in Lovd as [Likely_benign]. Variant chr7-44188923-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00615 (937/152282) while in subpopulation AFR AF= 0.0219 (908/41548). AF 95% confidence interval is 0.0207. There are 9 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5 linkuse as main transcript	c.31G>A	p.Ala11Thr	missense_variant	1/10	ENST00000403799.8
GCK	NM_001354800.1 linkuse as main transcript	c.31G>A	p.Ala11Thr	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8 linkuse as main transcript	c.31G>A	p.Ala11Thr	missense_variant	1/10	1	NM_000162.5	P1	P35557-1

Frequencies

GnomAD3 genomes

AF:

0.00615

AC:

936

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00166

AC:

415

AN:

250754

Hom.:

AF XY:

0.00125

AC XY:

170

AN XY:

135544

show subpopulations

Gnomad AFR exome

AF:

0.0238

Gnomad AMR exome

AF:

0.000724

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000670

AC:

979

AN:

1461600

Hom.:

Cov.:

AF XY:

0.000553

AC XY:

402

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0253

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.000994

GnomAD4 genome

AF:

0.00615

AC:

937

AN:

152282

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

421

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0219

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.00688

ESP6500AA

AF:

0.0227

AC:

100

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00213

AC:

258

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2020	This variant is associated with the following publications: (PMID: 18271687, 19228875, 8454109, 14517946, 17573900, 23506826, 19790256, 11508276, 29056535) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 17, 2013	- -

Maturity onset diabetes mellitus in young

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Aug 12, 2016

ACMG Criteria:BP4, BS1 (3% in Africans in 1000g) , BS2(type2diabetesgenetics.org 61 cases and 49 controls, 3 homozygotes in ExAC); 6/503 TODAY, BP6 (Chicago calls benign) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Benign

4.9

DANN

Benign

0.86

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.11

T;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

1.0

N;N

PROVEAN

Benign

0.020

N;N

REVEL

Uncertain

0.31

Sift

Benign

0.55

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0020

B;.

Vest4

0.064

MVP

0.81

ClinPred

0.0043

GERP RS

-2.5

Varity_R

0.044

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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