2-27508073-T-C

Variant names:

Variant summary

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

The NM_001486.4(GCKR):c.1337T>C(p.Leu446Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,610,248 control chromosomes in the GnomAD database, including 312,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.67 ( 35431 hom., cov: 31)

Exomes 𝑓: 0.61 ( 277034 hom. )

Consequence

GCKR
NM_001486.4 missense, splice_region

Scores

Splicing: ADA: 0.000004368

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 0.0750

Publications

1182 publications found

Variant links:

Genes affected

GCKR (HGNC:4196): (glucokinase regulator) This gene encodes a protein belonging to the GCKR subfamily of the SIS (Sugar ISomerase) family of proteins. The gene product is a regulatory protein that inhibits glucokinase in liver and pancreatic islet cells by binding non-covalently to form an inactive complex with the enzyme. This gene is considered a susceptibility gene candidate for a form of maturity-onset diabetes of the young (MODY). [provided by RefSeq, Jul 2008]

GCKR 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 (MetaRNN=1.074255E-6).

BP6

Variant 2-27508073-T-C is Benign according to our data. Variant chr2-27508073-T-C is described in ClinVar as Benign. ClinVar VariationId is 8751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GCKR	NM_001486.4 link	c.1337T>C	p.Leu446Pro	missense_variant, splice_region_variant	Exon 15 of 19	ENST00000264717.7	NP_001477.2
GCKR	XM_017003796.2 link	c.767T>C	p.Leu256Pro	missense_variant, splice_region_variant	Exon 10 of 14		XP_016859285.1
GCKR	XM_017003797.2 link	c.767T>C	p.Leu256Pro	missense_variant, splice_region_variant	Exon 9 of 13		XP_016859286.1
GCKR	XR_001738699.1 link	n.*5T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GCKR	ENST00000264717.7 link	c.1337T>C	p.Leu446Pro	missense_variant, splice_region_variant	Exon 15 of 19	1	NM_001486.4	ENSP00000264717.2
GCKR	ENST00000411584.1 link	c.437T>C	p.Leu146Pro	missense_variant, splice_region_variant	Exon 5 of 7	3		ENSP00000416917.1
GCKR	ENST00000478147.1 link	n.534T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.670

AC:

101762

AN:

151894

Hom.:

35360

Cov.:

show subpopulations

Gnomad AFR

AF:

0.858

Gnomad AMI

AF:

0.708

Gnomad AMR

AF:

0.626

Gnomad ASJ

AF:

0.459

Gnomad EAS

AF:

0.501

Gnomad SAS

AF:

0.757

Gnomad FIN

AF:

0.638

Gnomad MID

AF:

0.490

Gnomad NFE

AF:

0.590

Gnomad OTH

AF:

0.611

GnomAD2 exomes

AF:

0.633

AC:

159003

AN:

251160

AF XY:

0.631

show subpopulations

Gnomad AFR exome

AF:

0.868

Gnomad AMR exome

AF:

0.666

Gnomad ASJ exome

AF:

0.467

Gnomad EAS exome

AF:

0.511

Gnomad FIN exome

AF:

0.643

Gnomad NFE exome

AF:

0.590

Gnomad OTH exome

AF:

0.600

GnomAD4 exome

AF:

0.612

AC:

892119

AN:

1458234

Hom.:

277034

Cov.:

AF XY:

0.613

AC XY:

445037

AN XY:

725598

show subpopulations

African (AFR)

AF:

0.863

AC:

28862

AN:

33428

American (AMR)

AF:

0.665

AC:

29720

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.467

AC:

12201

AN:

26112

East Asian (EAS)

AF:

0.468

AC:

18556

AN:

39666

South Asian (SAS)

AF:

0.753

AC:

64859

AN:

86174

European-Finnish (FIN)

AF:

0.646

AC:

34519

AN:

53416

Middle Eastern (MID)

AF:

0.502

AC:

2891

AN:

5762

European-Non Finnish (NFE)

AF:

0.599

AC:

663691

AN:

1108704

Other (OTH)

AF:

0.611

AC:

36820

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

18320

36640

54960

73280

91600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18250

36500

54750

73000

91250

<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:

0.670

AC:

101903

AN:

152014

Hom.:

35431

Cov.:

AF XY:

0.669

AC XY:

49718

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.859

AC:

35623

AN:

41488

American (AMR)

AF:

0.626

AC:

9556

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.459

AC:

1591

AN:

3470

East Asian (EAS)

AF:

0.501

AC:

2581

AN:

5150

South Asian (SAS)

AF:

0.757

AC:

3651

AN:

4820

European-Finnish (FIN)

AF:

0.638

AC:

6739

AN:

10566

Middle Eastern (MID)

AF:

0.493

AC:

144

AN:

292

European-Non Finnish (NFE)

AF:

0.590

AC:

40075

AN:

67950

Other (OTH)

AF:

0.615

AC:

1297

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1578

3155

4733

6310

7888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

800

1600

2400

3200

4000

<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:

0.604

Hom.:

101372

Bravo

AF:

0.674

TwinsUK

AF:

0.600

AC:

2226

ALSPAC

AF:

0.594

AC:

2290

ESP6500AA

AF:

0.857

AC:

3776

ESP6500EA

AF:

0.583

AC:

5015

ExAC

AF:

0.642

AC:

77990

Asia WGS

AF:

0.695

AC:

2412

AN:

3478

EpiCase

AF:

0.552

EpiControl

AF:

0.553

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 33588820, 28082259, 24918535, 22001757, 31118516, 30297969, 30315176, 30420299, 29632382, 29083407, 27516387, 27798624, 23586973, 28385800, 27346689, 26174136, 26043229, 26551672, 27398621, 28008009, 18556336, 23383164, 23894584, 21674002, 21423719, 22182842, 21525158, 19526250, 19643913, 24879641, 22038520, 18678614, 22958899) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 5

Other:1

Feb 01, 2010

OMIM

Significance:association

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.035

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.040

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.031

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0000011

MetaSVM

Benign

-1.0

PhyloP100

0.075

PrimateAI

Benign

0.48

PROVEAN

Benign

2.4

REVEL

Benign

0.080

Sift

Benign

1.0

Sift4G

Benign

0.75

Vest4

0.034

MPC

0.087

ClinPred

0.0021

GERP RS

3.0

gMVP

0.37

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000044

dbscSNV1_RF

Benign

0.0040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over