2-27497355-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001486.4(GCKR):​c.172G>A​(p.Ala58Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

GCKR
NM_001486.4 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.03
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23122558).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GCKRNM_001486.4 linkuse as main transcriptc.172G>A p.Ala58Thr missense_variant 2/19 ENST00000264717.7
GCKRXM_011532763.1 linkuse as main transcriptc.172G>A p.Ala58Thr missense_variant 2/13
GCKRXR_001738699.1 linkuse as main transcriptn.238G>A non_coding_transcript_exon_variant 2/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GCKRENST00000264717.7 linkuse as main transcriptc.172G>A p.Ala58Thr missense_variant 2/191 NM_001486.4 P1
GCKRENST00000472290.1 linkuse as main transcriptn.194G>A non_coding_transcript_exon_variant 2/111
GCKRENST00000453813.1 linkuse as main transcriptc.88G>A p.Ala30Thr missense_variant 1/83
GCKRENST00000417872.5 linkuse as main transcriptn.229G>A non_coding_transcript_exon_variant 2/74

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251490
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000435
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461888
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000277
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 17, 2023Does not currently meet published gene-disease clinical validity criteria Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 23, 2023In 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCKR protein function. ClinVar contains an entry for this variant (Variation ID: 2547744). This variant has not been reported in the literature in individuals affected with GCKR-related conditions. This variant is present in population databases (rs777420998, gnomAD 0.05%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 58 of the GCKR protein (p.Ala58Thr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.30
T;T
Eigen
Benign
0.19
Eigen_PC
Benign
0.12
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.23
T;T
MetaSVM
Uncertain
-0.14
T
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.8
N;N
REVEL
Uncertain
0.47
Sift
Uncertain
0.016
D;D
Sift4G
Benign
0.077
T;T
Vest4
0.41
MutPred
0.36
Loss of sheet (P = 0.0817);.;
MVP
0.88
MPC
0.35
ClinPred
0.30
T
GERP RS
2.4
gMVP
0.32

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs777420998; hg19: chr2-27720222; API