chr2-27508073-T-C

Variant names:

• chr2-27508073-T-C
• rs1260326
• NM_001486.4:c.1337T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 the same amino acid substitution has been previously reported as Likely benign in 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:3 O:1
• Conservation: PhyloP100: 0.0750
• Publications: 1182 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001486.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCKR	NM_001486.4	MANE Select	c.1337T>C	p.Leu446Pro	missense splice_region	Exon 15 of 19	NP_001477.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCKR	ENST00000264717.7	TSL:1 MANE Select	c.1337T>C	p.Leu446Pro	missense splice_region	Exon 15 of 19	ENSP00000264717.2
	GCKR	ENST00000411584.1	TSL:3	c.437T>C	p.Leu146Pro	missense splice_region	Exon 5 of 7	ENSP00000416917.1
	GCKR	ENST00000478147.1	TSL:5	n.534T>C		splice_region non_coding_transcript_exon	Exon 2 of 3

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

GnomAD2 exomes AF: 0.633 AC: 159003 AN: 251160 AF XY: 0.631

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 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

African (AFR) AF: 0.863 AC: 28862 AN: 33428

American (AMR) AF: 0.665 AC: 29720 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 12201 AN: 26112

East Asian (EAS) AF: 0.468 AC: 18556 AN: 39666

South Asian (SAS) AF: 0.753 AC: 64859 AN: 86174

European-Finnish (FIN) AF: 0.646 AC: 34519 AN: 53416

Middle Eastern (MID) AF: 0.502 AC: 2891 AN: 5762

European-Non Finnish (NFE) AF: 0.599 AC: 663691 AN: 1108704

Other (OTH) AF: 0.611 AC: 36820 AN: 60264

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

African (AFR) AF: 0.859 AC: 35623 AN: 41488

American (AMR) AF: 0.626 AC: 9556 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1591 AN: 3470

East Asian (EAS) AF: 0.501 AC: 2581 AN: 5150

South Asian (SAS) AF: 0.757 AC: 3651 AN: 4820

European-Finnish (FIN) AF: 0.638 AC: 6739 AN: 10566

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.590 AC: 40075 AN: 67950

Other (OTH) AF: 0.615 AC: 1297 AN: 2110

Alfa AF: 0.604 Hom.: 101372

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:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 01, 2010

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.075
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
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1260326; hg19: chr2-27730940; COSMIC: COSV53108202; COSMIC: COSV53108202;