rs1260326

chr2-27508073-T-Cchr2-27508073-T-G

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.1337T>C(p.Leu446Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,610,248 control chromosomes in the GnomAD database, including 312,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.67 (35431 hom., cov: 31)
  • Exomes 𝑓: 0.61 (277034 hom.)
• Consequence: GCKR NM_001486.4 missense, splice_region
• Scores: Splicing: ADA: 0.000004368
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.0750

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 (MetaRNN=1.074255E-6).
• BP6: Variant 2-27508073-T-C is Benign according to our data. Variant chr2-27508073-T-C is described in ClinVar as [Benign]. Clinvar id is 8751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCKR	NM_001486.4	c.1337T>C	p.Leu446Pro	missense_variant, splice_region_variant	15/19	ENST00000264717.7
GCKR	XM_017003796.2	c.767T>C	p.Leu256Pro	missense_variant, splice_region_variant	10/14
GCKR	XM_017003797.2	c.767T>C	p.Leu256Pro	missense_variant, splice_region_variant	9/13
GCKR	XR_001738699.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCKR	ENST00000264717.7	c.1337T>C	p.Leu446Pro	missense_variant, splice_region_variant	15/19	1	NM_001486.4	P1
GCKR	ENST00000411584.1	c.440T>C	p.Leu147Pro	missense_variant, splice_region_variant	5/7	3
GCKR	ENST00000478147.1	n.534T>C		splice_region_variant, non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101762 AN: 151894 Hom.: 35360 Cov.: 31

Gnomad AFR AF: 0.858

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.611

GnomAD3 exomes AF: 0.633 AC: 159003 AN: 251160 Hom.: 51710 AF XY: 0.631 AC XY: 85704 AN XY: 135752

Gnomad AFR exome AF: 0.868

Gnomad AMR exome AF: 0.666

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.511

Gnomad SAS exome AF: 0.758

Gnomad FIN exome AF: 0.643

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.612 AC: 892119 AN: 1458234 Hom.: 277034 Cov.: 34 AF XY: 0.613 AC XY: 445037 AN XY: 725598

Gnomad4 AFR exome AF: 0.863

Gnomad4 AMR exome AF: 0.665

Gnomad4 ASJ exome AF: 0.467

Gnomad4 EAS exome AF: 0.468

Gnomad4 SAS exome AF: 0.753

Gnomad4 FIN exome AF: 0.646

Gnomad4 NFE exome AF: 0.599

Gnomad4 OTH exome AF: 0.611

GnomAD4 genome AF: 0.670 AC: 101903 AN: 152014 Hom.: 35431 Cov.: 31 AF XY: 0.669 AC XY: 49718 AN XY: 74306

Gnomad4 AFR AF: 0.859

Gnomad4 AMR AF: 0.626

Gnomad4 ASJ AF: 0.459

Gnomad4 EAS AF: 0.501

Gnomad4 SAS AF: 0.757

Gnomad4 FIN AF: 0.638

Gnomad4 NFE AF: 0.590

Gnomad4 OTH AF: 0.615

Alfa AF: 0.591 Hom.: 66863

Bravo AF: 0.674

TwinsUK AF: 0.600 AC: 2226

ALSPAC AF: 0.594 AC: 2290

ESP6500AA AF: 0.857 AC: 3776

ESP6500EA AF: 0.583 AC: 5015

ExAC AF: 0.642 AC: 77990

Asia WGS AF: 0.695 AC: 2412 AN: 3478

EpiCase AF: 0.552

EpiControl AF: 0.553

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2018	This variant is associated with the following publications: (PMID: 33588820, 28082259, 24918535, 22001757, 31118516, 30297969, 30315176, 30420299, 29632382, 29083407, 27516387, 27798624, 23586973, 28385800, 27346689, 26174136, 26043229, 26551672, 27398621, 28008009, 18556336, 23383164, 23894584, 21674002, 21423719, 22182842, 21525158, 19526250, 19643913, 24879641, 22038520, 18678614, 22958899) -

Fasting plasma glucose level quantitative trait locus 5 Other:1

association, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.035
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.040
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.27	P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.080
Sift	Benign	1.0	T
Sift4G	Benign	0.75	T
Vest4		0.034
MPC		0.087
ClinPred		0.0021	T
GERP RS		3.0
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000044
dbscSNV1_RF	Benign	0.0040
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: rs1260326; hg19: chr2-27730940; COSMIC: COSV53108202; COSMIC: COSV53108202;