rs2268574

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000162.5(GCK):c.679+38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,592,566 control chromosomes in the GnomAD database, including 207,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.57 ( 25486 hom., cov: 32)

Exomes 𝑓: 0.50 ( 181745 hom. )

Consequence

GCK
NM_000162.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.77

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

hyperinsulinism due to glucokinase deficiency
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
maturity-onset diabetes of the young type 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
permanent neonatal diabetes mellitus 1
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
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

GCK links:

LOC105375258 (HGNC:):

LOC105375258 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 7-44149722-A-G is Benign according to our data. Variant chr7-44149722-A-G is described in ClinVar as Benign. ClinVar VariationId is 673534.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCK	NM_000162.5	MANE Select	c.679+38T>C	intron	N/A	NP_000153.1	Q53Y25
GCK	NM_033507.3		c.682+38T>C	intron	N/A	NP_277042.1	P35557-2
GCK	NM_033508.3		c.676+38T>C	intron	N/A	NP_277043.1	P35557-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCK	ENST00000403799.8	TSL:1 MANE Select	c.679+38T>C	intron	N/A	ENSP00000384247.3	P35557-1
GCK	ENST00000395796.8	TSL:1	n.*677+38T>C	intron	N/A	ENSP00000379142.4	A0A8C8KJG0
GCK	ENST00000671824.1		c.679+38T>C	intron	N/A	ENSP00000500264.1	A0A5F9ZHE0

Frequencies

GnomAD3 genomes

AF:

0.570

AC:

86483

AN:

151798

Hom.:

25462

Cov.:

show subpopulations

Gnomad AFR

AF:

0.729

Gnomad AMI

AF:

0.501

Gnomad AMR

AF:

0.567

Gnomad ASJ

AF:

0.503

Gnomad EAS

AF:

0.630

Gnomad SAS

AF:

0.437

Gnomad FIN

AF:

0.495

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.495

Gnomad OTH

AF:

0.558

GnomAD2 exomes

AF:

0.531

AC:

132823

AN:

250270

AF XY:

0.518

show subpopulations

Gnomad AFR exome

AF:

0.732

Gnomad AMR exome

AF:

0.595

Gnomad ASJ exome

AF:

0.495

Gnomad EAS exome

AF:

0.661

Gnomad FIN exome

AF:

0.497

Gnomad NFE exome

AF:

0.497

Gnomad OTH exome

AF:

0.527

GnomAD4 exome

AF:

0.499

AC:

718976

AN:

1440652

Hom.:

181745

Cov.:

AF XY:

0.496

AC XY:

356115

AN XY:

717960

show subpopulations

African (AFR)

AF:

0.735

AC:

24296

AN:

33078

American (AMR)

AF:

0.593

AC:

26488

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.498

AC:

12958

AN:

26016

East Asian (EAS)

AF:

0.631

AC:

24985

AN:

39578

South Asian (SAS)

AF:

0.431

AC:

36946

AN:

85712

European-Finnish (FIN)

AF:

0.500

AC:

26452

AN:

52934

Middle Eastern (MID)

AF:

0.477

AC:

2732

AN:

5722

European-Non Finnish (NFE)

AF:

0.488

AC:

534088

AN:

1093366

Other (OTH)

AF:

0.504

AC:

30031

AN:

59608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

20087

40175

60262

80350

100437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15702

31404

47106

62808

78510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.570

AC:

86554

AN:

151914

Hom.:

25486

Cov.:

AF XY:

0.569

AC XY:

42208

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.729

AC:

30213

AN:

41456

American (AMR)

AF:

0.567

AC:

8655

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.503

AC:

1740

AN:

3462

East Asian (EAS)

AF:

0.630

AC:

3240

AN:

5140

South Asian (SAS)

AF:

0.436

AC:

2094

AN:

4808

European-Finnish (FIN)

AF:

0.495

AC:

5225

AN:

10552

Middle Eastern (MID)

AF:

0.490

AC:

143

AN:

292

European-Non Finnish (NFE)

AF:

0.495

AC:

33615

AN:

67912

Other (OTH)

AF:

0.557

AC:

1173

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1837

3675

5512

7350

9187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

720

1440

2160

2880

3600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.541

Hom.:

4778

Bravo

AF:

0.585

Asia WGS

AF:

0.524

AC:

1822

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.19

(source)

DANN

Benign

0.26

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over