rs3817588

Variant names:

• chr2-27508345-T-C
• rs3817588
• NM_001486.4:c.1422+94T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001486.4(GCKR):​c.1422+94T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 867,660 control chromosomes in the GnomAD database, including 17,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2241 hom., cov: 32)
  • Exomes 𝑓: 0.20 (15214 hom.)
• Consequence: GCKR NM_001486.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.558
• Publications: 39 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-27508345-T-C is Benign according to our data. Variant chr2-27508345-T-C is described in ClinVar as [Benign]. Clinvar id is 1283523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCKR	NM_001486.4	c.1422+94T>C		intron_variant	Intron 16 of 18	ENST00000264717.7	NP_001477.2
GCKR	XM_017003796.2	c.852+94T>C		intron_variant	Intron 11 of 13		XP_016859285.1
GCKR	XM_017003797.2	c.852+94T>C		intron_variant	Intron 10 of 12		XP_016859286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCKR	ENST00000264717.7	c.1422+94T>C		intron_variant	Intron 16 of 18	1	NM_001486.4	ENSP00000264717.2
GCKR	ENST00000411584.1	c.522+94T>C		intron_variant	Intron 6 of 6	3		ENSP00000416917.1
GCKR	ENST00000478147.1	n.*134T>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22586 AN: 152010 Hom.: 2243 Cov.: 32

Gnomad AFR AF: 0.0369

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.196 AC: 140361 AN: 715532 Hom.: 15214 AF XY: 0.200 AC XY: 76530 AN XY: 382518

African (AFR) AF: 0.0341 AC: 655 AN: 19192

American (AMR) AF: 0.0819 AC: 3373 AN: 41164

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 2759 AN: 21026

East Asian (EAS) AF: 0.321 AC: 11589 AN: 36072

South Asian (SAS) AF: 0.260 AC: 18147 AN: 69842

European-Finnish (FIN) AF: 0.249 AC: 12233 AN: 49182

Middle Eastern (MID) AF: 0.0869 AC: 362 AN: 4164

European-Non Finnish (NFE) AF: 0.193 AC: 84703 AN: 439200

Other (OTH) AF: 0.183 AC: 6540 AN: 35690

GnomAD4 genome AF: 0.148 AC: 22585 AN: 152128 Hom.: 2241 Cov.: 32 AF XY: 0.154 AC XY: 11426 AN XY: 74344

African (AFR) AF: 0.0368 AC: 1529 AN: 41544

American (AMR) AF: 0.103 AC: 1582 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 444 AN: 3470

East Asian (EAS) AF: 0.337 AC: 1740 AN: 5160

South Asian (SAS) AF: 0.258 AC: 1240 AN: 4814

European-Finnish (FIN) AF: 0.244 AC: 2579 AN: 10570

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12937 AN: 67954

Other (OTH) AF: 0.134 AC: 283 AN: 2114

Alfa AF: 0.165 Hom.: 4121

Bravo AF: 0.131

Asia WGS AF: 0.300 AC: 1040 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.55
DANN	Benign	0.41
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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: rs3817588; hg19: chr2-27731212; COSMIC: COSV107284784; COSMIC: COSV107284784;