2-27508073-T-C

Position:

chr2-27508073-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 (★★).

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

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 made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein
GCKR	NM_001486.4 linkuse as main transcript	c.1337T>C	p.Leu446Pro	missense_variant, splice_region_variant	15/19	ENST00000264717.7	NP_001477.2
GCKR	XM_017003796.2 linkuse as main transcript	c.767T>C	p.Leu256Pro	missense_variant, splice_region_variant	10/14		XP_016859285.1
GCKR	XM_017003797.2 linkuse as main transcript	c.767T>C	p.Leu256Pro	missense_variant, splice_region_variant	9/13		XP_016859286.1
GCKR	XR_001738699.1 linkuse as main transcript			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GCKR	ENST00000264717.7 linkuse as main transcript	c.1337T>C	p.Leu446Pro	missense_variant, splice_region_variant	15/19	1	NM_001486.4	ENSP00000264717	P1
GCKR	ENST00000411584.1 linkuse as main transcript	c.440T>C	p.Leu147Pro	missense_variant, splice_region_variant	5/7	3		ENSP00000416917
GCKR	ENST00000478147.1 linkuse as main transcript	n.534T>C		splice_region_variant, non_coding_transcript_exon_variant	2/3	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

GnomAD3 exomes

AF:

0.633

AC:

159003

AN:

251160

Hom.:

51710

AF XY:

0.631

AC XY:

85704

AN XY:

135752

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 SAS exome

AF:

0.758

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

Gnomad4 AFR exome

AF:

0.863

Gnomad4 AMR exome

AF:

0.665

Gnomad4 ASJ exome

AF:

0.467

Gnomad4 EAS exome

AF:

0.468

Gnomad4 SAS exome

AF:

0.753

Gnomad4 FIN exome

AF:

0.646

Gnomad4 NFE exome

AF:

0.599

Gnomad4 OTH exome

AF:

0.611

GnomAD4 genome

AF:

0.670

AC:

101903

AN:

152014

Hom.:

35431

Cov.:

AF XY:

0.669

AC XY:

49718

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.859

Gnomad4 AMR

AF:

0.626

Gnomad4 ASJ

AF:

0.459

Gnomad4 EAS

AF:

0.501

Gnomad4 SAS

AF:

0.757

Gnomad4 FIN

AF:

0.638

Gnomad4 NFE

AF:

0.590

Gnomad4 OTH

AF:

0.615

Alfa

AF:

0.591

Hom.:

66863

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2018	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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fasting plasma glucose level quantitative trait locus 5

Other:1

association, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

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

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

MutationTaster

Benign

0.27

P;P

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

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

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