rs146175795

chr2-27498276-G-Achr2-27498276-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1
• 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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013950884).
• BS2: High Homozygotes in GnomAd 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: 253 AN: 152164 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00926

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00268 AC: 674 AN: 251402 Hom.: 5 AF XY: 0.00213 AC XY: 289 AN XY: 135890

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00848

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000876 AC: 1280 AN: 1461350 Hom.: 8 Cov.: 30 AF XY: 0.000798 AC XY: 580 AN XY: 727000

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0147

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0134

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.00166 AC: 253 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74460

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00928

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000534 Hom.: 0

Bravo AF: 0.00283

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00228 AC: 277

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	0.13	D
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.065	T;T
Vest4		0.82
MVP		0.87
MPC		0.36
ClinPred		0.83	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146175795; hg19: chr2-27721143;