7-44145489-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000162.5(GCK):c.1253+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,592,264 control chromosomes in the GnomAD database, including 47,418 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 11807 hom., cov: 34)

Exomes 𝑓: 0.20 ( 35611 hom. )

Consequence

GCK
NM_000162.5 splice_region, intron

Scores

Splicing: ADA: 0.0009073

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.451

Publications

25 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:

ENSG00000300758 (HGNC:):

ENSG00000300758 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 7-44145489-G-A is Benign according to our data. Variant chr7-44145489-G-A is described in ClinVar as Benign. ClinVar VariationId is 129147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.651 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.1253+8C>T	splice_region intron	N/A	NP_000153.1	Q53Y25
GCK	NM_033507.3		c.1256+8C>T	splice_region intron	N/A	NP_277042.1	P35557-2
GCK	NM_033508.3		c.1250+8C>T	splice_region 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.1253+8C>T	splice_region intron	N/A	ENSP00000384247.3	P35557-1
GCK	ENST00000395796.8	TSL:1	n.*1251+8C>T	splice_region intron	N/A	ENSP00000379142.4	A0A8C8KJG0
GCK	ENST00000459642.1	TSL:1	n.633+8C>T	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.335

AC:

50947

AN:

152062

Hom.:

11776

Cov.:

show subpopulations

Gnomad AFR

AF:

0.658

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.283

Gnomad ASJ

AF:

0.169

Gnomad EAS

AF:

0.387

Gnomad SAS

AF:

0.301

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.279

GnomAD2 exomes

AF:

0.270

AC:

59821

AN:

221712

AF XY:

0.259

show subpopulations

Gnomad AFR exome

AF:

0.672

Gnomad AMR exome

AF:

0.311

Gnomad ASJ exome

AF:

0.169

Gnomad EAS exome

AF:

0.433

Gnomad FIN exome

AF:

0.238

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.220

GnomAD4 exome

AF:

0.202

AC:

291080

AN:

1440084

Hom.:

35611

Cov.:

AF XY:

0.203

AC XY:

144864

AN XY:

713972

show subpopulations

African (AFR)

AF:

0.680

AC:

22521

AN:

33138

American (AMR)

AF:

0.306

AC:

13068

AN:

42712

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

4378

AN:

25818

East Asian (EAS)

AF:

0.389

AC:

15119

AN:

38880

South Asian (SAS)

AF:

0.283

AC:

23894

AN:

84386

European-Finnish (FIN)

AF:

0.238

AC:

11825

AN:

49644

Middle Eastern (MID)

AF:

0.212

AC:

1193

AN:

5620

European-Non Finnish (NFE)

AF:

0.169

AC:

185850

AN:

1100430

Other (OTH)

AF:

0.223

AC:

13232

AN:

59456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

14579

29158

43738

58317

72896

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6946

13892

20838

27784

34730

<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:

0.335

AC:

51020

AN:

152180

Hom.:

11807

Cov.:

AF XY:

0.337

AC XY:

25049

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.658

AC:

27289

AN:

41490

American (AMR)

AF:

0.283

AC:

4330

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

586

AN:

3470

East Asian (EAS)

AF:

0.387

AC:

2000

AN:

5164

South Asian (SAS)

AF:

0.299

AC:

1445

AN:

4826

European-Finnish (FIN)

AF:

0.233

AC:

2475

AN:

10604

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.178

AC:

12137

AN:

68000

Other (OTH)

AF:

0.278

AC:

589

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1495

2990

4485

5980

7475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

470

940

1410

1880

2350

<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:

0.243

Hom.:

4273

Bravo

AF:

0.353

Asia WGS

AF:

0.330

AC:

1147

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Maturity-onset diabetes of the young (2)

not provided (2)

not specified (2)

Hyperinsulinism due to glucokinase deficiency (1)

Maturity-onset diabetes of the young type 2 (1)

Permanent neonatal diabetes mellitus (1)

Transient Neonatal Diabetes, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.8

(source)

DANN

Benign

0.95

PhyloP100

0.45

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00091

dbscSNV1_RF

Benign

0.0020

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

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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