chr2-27496919-A-ACGGTTT

Variant names:

• chr2-27496919-A-ACGGTTT
• rs748731892
• NM_001486.4:c.17_22dupGGTTTC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -1.26

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]

ACMG classification

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	c.17_22dupGGTTTC	p.Arg6_Phe7dup	disruptive_inframe_insertion	Exon 1 of 19	ENST00000264717.7	NP_001477.2
GCKR	XM_011532763.1	c.17_22dupGGTTTC	p.Arg6_Phe7dup	disruptive_inframe_insertion	Exon 1 of 13		XP_011531065.1
GCKR	XR_001738699.1	n.83_88dupGGTTTC		non_coding_transcript_exon_variant	Exon 1 of 13

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152108 Hom.: 0 Cov.: 32

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: 42 AN: 251462 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135906

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.: 0 Cov.: 30 AF XY: 0.000204 AC XY: 148 AN XY: 727144

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: 23 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74426

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.: 0

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

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 15, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2024	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) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fasting plasma glucose level quantitative trait locus 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs748731892; hg19: chr2-27719786;