chr2-27508073-T-G

Variant names:

• chr2-27508073-T-G
• rs1260326
• NM_001486.4:c.1337T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001486.4(GCKR):​c.1337T>G​(p.Leu446Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L446P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GCKR NM_001486.4 missense, splice_region
• Scores: Splicing: ADA: 0.0004077
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750
• Publications: 1182 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16724753).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001486.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCKR	NM_001486.4	MANE Select	c.1337T>G	p.Leu446Arg	missense splice_region	Exon 15 of 19	NP_001477.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCKR	ENST00000264717.7	TSL:1 MANE Select	c.1337T>G	p.Leu446Arg	missense splice_region	Exon 15 of 19	ENSP00000264717.2
	GCKR	ENST00000411584.1	TSL:3	c.437T>G	p.Leu146Arg	missense splice_region	Exon 5 of 7	ENSP00000416917.1
	GCKR	ENST00000478147.1	TSL:5	n.534T>G		splice_region non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251160 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.075
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.092
Sift	Benign	0.20	T
Sift4G	Benign	0.38	T
Vest4		0.13
MVP		0.31
MPC		0.079
ClinPred		0.093	T
GERP RS		3.0
gMVP		0.26
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs1260326; hg19: chr2-27730940;