rs813592

Positions:

• chr2-27499104-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001486.4(GCKR):​c.429-38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,301,156 control chromosomes in the GnomAD database, including 112,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18031 hom., cov: 32)
  • Exomes 𝑓: 0.40 (94701 hom.)
• Consequence: GCKR NM_001486.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.112

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-27499104-T-C is Benign according to our data. Variant chr2-27499104-T-C is described in ClinVar as [Benign]. Clinvar id is 1275596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCKR	NM_001486.4	c.429-38T>C		intron_variant		ENST00000264717.7	NP_001477.2
GCKR	XM_011532763.1	c.429-38T>C		intron_variant			XP_011531065.1
GCKR	XM_017003796.2	c.-75-293T>C		intron_variant			XP_016859285.1
GCKR	XR_001738699.1	n.495-38T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCKR	ENST00000264717.7	c.429-38T>C		intron_variant		1	NM_001486.4	ENSP00000264717	P1
GCKR	ENST00000472290.1	n.451-38T>C		intron_variant, non_coding_transcript_variant		1
GCKR	ENST00000453813.1	c.345-38T>C		intron_variant		3		ENSP00000399463
GCKR	ENST00000417872.5	n.486-293T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70708 AN: 151918 Hom.: 17988 Cov.: 32

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.412

GnomAD3 exomes AF: 0.417 AC: 104282 AN: 249880 Hom.: 23554 AF XY: 0.407 AC XY: 54987 AN XY: 135072

Gnomad AFR exome AF: 0.679

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.423

Gnomad FIN exome AF: 0.428

Gnomad NFE exome AF: 0.383

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.397 AC: 456416 AN: 1149120 Hom.: 94701 Cov.: 16 AF XY: 0.395 AC XY: 231792 AN XY: 586844

Gnomad4 AFR exome AF: 0.681

Gnomad4 AMR exome AF: 0.555

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.419

Gnomad4 FIN exome AF: 0.433

Gnomad4 NFE exome AF: 0.389

Gnomad4 OTH exome AF: 0.396

GnomAD4 genome AF: 0.466 AC: 70811 AN: 152036 Hom.: 18031 Cov.: 32 AF XY: 0.464 AC XY: 34500 AN XY: 74328

Gnomad4 AFR AF: 0.671

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.339

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.429

Gnomad4 NFE AF: 0.383

Gnomad4 OTH AF: 0.415

Alfa AF: 0.407 Hom.: 4258

Bravo AF: 0.476

Asia WGS AF: 0.364 AC: 1264 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.8
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs813592; hg19: chr2-27721971; COSMIC: COSV53022863; COSMIC: COSV53022863;