rs1260326

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-27508073-T-A
• chr2-27508073-T-C
• chr2-27508073-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001486.4(GCKR):​c.1337T>A​(p.Leu446Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GCKR NM_001486.4 missense, splice_region
• Scores: Splicing: ADA: 0.00002573
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750

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 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=0.17752084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCKR	NM_001486.4	c.1337T>A	p.Leu446Gln	missense_variant, splice_region_variant	Exon 15 of 19	ENST00000264717.7	NP_001477.2
GCKR	XM_017003796.2	c.767T>A	p.Leu256Gln	missense_variant, splice_region_variant	Exon 10 of 14		XP_016859285.1
GCKR	XM_017003797.2	c.767T>A	p.Leu256Gln	missense_variant, splice_region_variant	Exon 9 of 13		XP_016859286.1
GCKR	XR_001738699.1	n.*5T>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCKR	ENST00000264717.7	c.1337T>A	p.Leu446Gln	missense_variant, splice_region_variant	Exon 15 of 19	1	NM_001486.4	ENSP00000264717.2
GCKR	ENST00000411584.1	c.437T>A	p.Leu146Gln	missense_variant, splice_region_variant	Exon 5 of 7	3		ENSP00000416917.1
GCKR	ENST00000478147.1	n.534T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459870 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726342

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.51
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.48	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.054
Sift	Benign	0.24	T
Sift4G	Benign	0.47	T
Vest4		0.20
MVP		0.31
MPC		0.063
ClinPred		0.081	T
GERP RS		3.0
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.072
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-27730940;