2-27497406-AAG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001486.4(GCKR):c.216+9_216+10del variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00702 in 1,614,048 control chromosomes in the GnomAD database, including 711 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (323 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (388 hom.)
• Consequence: GCKR NM_001486.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.60

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 -16 ACMG points.

• BP6: Variant 2-27497406-AAG-A is Benign according to our data. Variant chr2-27497406-AAG-A is described in ClinVar as [Benign]. Clinvar id is 1334327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCKR	NM_001486.4	c.216+9_216+10del		splice_region_variant, intron_variant		ENST00000264717.7
GCKR	XM_011532763.1	c.216+9_216+10del		splice_region_variant, intron_variant
GCKR	XR_001738699.1	n.282+9_282+10del		splice_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCKR	ENST00000264717.7	c.216+9_216+10del		splice_region_variant, intron_variant		1	NM_001486.4	P1
GCKR	ENST00000472290.1	n.238+9_238+10del		splice_region_variant, intron_variant, non_coding_transcript_variant		1
GCKR	ENST00000453813.1	c.132+9_132+10del		splice_region_variant, intron_variant		3
GCKR	ENST00000417872.5	n.273+9_273+10del		splice_region_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0368 AC: 5596 AN: 152136 Hom.: 319 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.00948 AC: 2383 AN: 251422 Hom.: 153 AF XY: 0.00703 AC XY: 956 AN XY: 135902

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00390 AC: 5696 AN: 1461794 Hom.: 388 AF XY: 0.00337 AC XY: 2449 AN XY: 727216

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.00626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000917

Gnomad4 OTH exome AF: 0.00838

GnomAD4 genome AF: 0.0370 AC: 5627 AN: 152254 Hom.: 323 Cov.: 32 AF XY: 0.0365 AC XY: 2716 AN XY: 74458

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0194 Hom.: 26

Bravo AF: 0.0425

Asia WGS AF: 0.0110 AC: 40 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

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	clinical testing	GeneDx	Jan 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs57332022; hg19: chr2-27720273;