Variant chr2-27496919-A-ACGGTTT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_001486.4(GCKR):c.17_22dupGGTTTC(p.Arg6_Phe7dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

GCKR
NM_001486.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -1.26

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001486.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCKR	NM_001486.4 link	c.17_22dupGGTTTC	p.Arg6_Phe7dup	disruptive_inframe_insertion	Exon 1 of 19	ENST00000264717.7	NP_001477.2	Q14397A0A0C4DFN2
GCKR	XM_011532763.1 link	c.17_22dupGGTTTC	p.Arg6_Phe7dup	disruptive_inframe_insertion	Exon 1 of 13		XP_011531065.1
GCKR	XR_001738699.1 link	n.83_88dupGGTTTC		non_coding_transcript_exon_variant	Exon 1 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GCKR	ENST00000264717.7 link	c.17_22dupGGTTTC	p.Arg6_Phe7dup	disruptive_inframe_insertion	Exon 1 of 19	1	NM_001486.4	ENSP00000264717.2	A0A0C4DFN2
GCKR	ENST00000472290.1 link	n.39_44dupGGTTTC		non_coding_transcript_exon_variant	Exon 1 of 11	1
GCKR	ENST00000417872.5 link	n.74_79dupGGTTTC		non_coding_transcript_exon_variant	Exon 1 of 7	4

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251462

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000205

AC:

299

AN:

1461600

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000239

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000151

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000145

Hom.:

Bravo

AF:

0.000155

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.17_22dup, results in the insertion of 2 amino acid(s) of the GCKR protein (p.Arg6_Phe7dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs748731892, gnomAD 0.02%). This variant has been observed in individual(s) with hypertriglyceridemia (PMID: 20657596). ClinVar contains an entry for this variant (Variation ID: 1303199). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant does not substantially affect GCKR function (PMID: 24879641). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Aug 12, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with hypertriglyceridemia, reported as p.Q8_H9insRF due to the use of alternate nomenclature; however, specific clinical information was not provided (PMID: 20657596); In-frame insertion of 2 amino acids in a non-repeat region; One in vitro functional study suggests that this variant has a mild impact on protein function and does not affect protein expression (PMID: 24879641); This variant is associated with the following publications: (PMID: 20657596, 34426522, 24879641, 36325899) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Fasting plasma glucose level quantitative trait locus 5

Uncertain:1

Oct 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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