NM_001486.4:c.307G>T

Variant names:

• chr2-27498276-G-T
• rs146175795
• NM_001486.4:c.307G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001486.4(GCKR):​c.307G>T​(p.Val103Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V103M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCKR NM_001486.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.05
• Publications: 17 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCKR	NM_001486.4	c.307G>T	p.Val103Leu	missense_variant	Exon 4 of 19	ENST00000264717.7	NP_001477.2
GCKR	XM_011532763.1	c.307G>T	p.Val103Leu	missense_variant	Exon 4 of 13		XP_011531065.1
GCKR	XR_001738699.1	n.373G>T		non_coding_transcript_exon_variant	Exon 4 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCKR	ENST00000264717.7	c.307G>T	p.Val103Leu	missense_variant	Exon 4 of 19	1	NM_001486.4	ENSP00000264717.2
GCKR	ENST00000472290.1	n.329G>T		non_coding_transcript_exon_variant	Exon 4 of 11	1
GCKR	ENST00000453813.1	c.223G>T	p.Val75Leu	missense_variant	Exon 3 of 8	3		ENSP00000399463.1
GCKR	ENST00000417872.5	n.364G>T		non_coding_transcript_exon_variant	Exon 4 of 7	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.029	D
PhyloP100		3.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.52
Sift	Benign	0.064	T;D
Sift4G	Uncertain	0.024	D;D
Vest4		0.58
MutPred		0.42		Gain of disorder (P = 0.1891);.;
MVP		0.86
MPC		0.30
ClinPred		0.88	D
GERP RS		2.9
gMVP		0.49
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs146175795; hg19: chr2-27721143;