chr2-27498276-G-A
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001486.4(GCKR):c.307G>A(p.Val103Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,613,632 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00088 ( 8 hom. )
Consequence
GCKR
NM_001486.4 missense
NM_001486.4 missense
Scores
1
11
5
Clinical Significance
Conservation
PhyloP100: 3.05
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.013950884).
BS2
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCKR | NM_001486.4 | c.307G>A | p.Val103Met | missense_variant | 4/19 | ENST00000264717.7 | |
GCKR | XM_011532763.1 | c.307G>A | p.Val103Met | missense_variant | 4/13 | ||
GCKR | XR_001738699.1 | n.373G>A | non_coding_transcript_exon_variant | 4/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCKR | ENST00000264717.7 | c.307G>A | p.Val103Met | missense_variant | 4/19 | 1 | NM_001486.4 | P1 | |
GCKR | ENST00000472290.1 | n.329G>A | non_coding_transcript_exon_variant | 4/11 | 1 | ||||
GCKR | ENST00000453813.1 | c.223G>A | p.Val75Met | missense_variant | 3/8 | 3 | |||
GCKR | ENST00000417872.5 | n.364G>A | non_coding_transcript_exon_variant | 4/7 | 4 |
Frequencies
GnomAD3 genomes AF: 0.00166 AC: 253AN: 152164Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00268 AC: 674AN: 251402Hom.: 5 AF XY: 0.00213 AC XY: 289AN XY: 135890
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GnomAD4 exome AF: 0.000876 AC: 1280AN: 1461350Hom.: 8 Cov.: 30 AF XY: 0.000798 AC XY: 580AN XY: 727000
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GnomAD4 genome AF: 0.00166 AC: 253AN: 152282Hom.: 2 Cov.: 32 AF XY: 0.00185 AC XY: 138AN XY: 74460
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Fasting plasma glucose level quantitative trait locus 5 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Hypertriglyceridemia Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The heterozygous p.Val103Met variant in GCKR has been identified in 2 individuals with hypertriglyceridaemia (PMID: 22182842), but has also been identified in >1% of Latino chromosomes and 3 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Val103Met variant may impact protein function (PMID: 22182842). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at