2-27497334-C-T

Position:

chr2-27497334-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001486.4(GCKR):c.151C>T(p.Arg51Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

GCKR
NM_001486.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: -0.542

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-27497334-C-T is Pathogenic according to our data. Variant chr2-27497334-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265524.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GCKR	NM_001486.4 linkuse as main transcript	c.151C>T	p.Arg51Ter	stop_gained	2/19	ENST00000264717.7
GCKR	XM_011532763.1 linkuse as main transcript	c.151C>T	p.Arg51Ter	stop_gained	2/13
GCKR	XR_001738699.1 linkuse as main transcript	n.217C>T		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GCKR	ENST00000264717.7 linkuse as main transcript	c.151C>T	p.Arg51Ter	stop_gained	2/19	1	NM_001486.4	P1
GCKR	ENST00000472290.1 linkuse as main transcript	n.173C>T		non_coding_transcript_exon_variant	2/11	1
GCKR	ENST00000453813.1 linkuse as main transcript	c.67C>T	p.Arg23Ter	stop_gained	1/8	3
GCKR	ENST00000417872.5 linkuse as main transcript	n.208C>T		non_coding_transcript_exon_variant	2/7	4

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251488

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000398

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 08, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2015	The R51X variant in the GCKR gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. However, a missense pathogenic variant at this same codon (R51G), as well as protein truncating pathogenic variants downstream of this variant, have been reported in the Human Gene Mutation Database in association with hypertriglyceridemia (Stenson et al., 2014), supporting both the functional importance of this region of the protein as well as the pathogenicity of more upstream truncating variants. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R51X variant was not observed at any significant frequency in approximately 6500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R51X variant is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.037

MutationTaster

Benign

1.0

A;N

Vest4

0.93

GERP RS

-1.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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