NM_001486.4:c.-9C>T

Variant names:

• chr2-27496896-C-T
• rs704794
• NM_001486.4:c.-9C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001486.4(GCKR):​c.-9C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000986 in 1,611,866 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (7 hom.)
• Consequence: GCKR NM_001486.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-27496896-C-T is Benign according to our data. Variant chr2-27496896-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1194950.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00498 (758/152224) while in subpopulation AFR AF = 0.0174 (721/41540). AF 95% confidence interval is 0.0163. There are 3 homozygotes in GnomAd4. There are 370 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCKR	NM_001486.4	MANE Select	c.-9C>T		5_prime_UTR	Exon 1 of 19	NP_001477.2	A0A0C4DFN2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCKR	ENST00000264717.7	TSL:1 MANE Select	c.-9C>T		5_prime_UTR	Exon 1 of 19	ENSP00000264717.2	A0A0C4DFN2
	GCKR	ENST00000472290.1	TSL:1	n.14C>T		non_coding_transcript_exon	Exon 1 of 11
	GCKR	ENST00000867122.1		c.-9C>T		5_prime_UTR	Exon 1 of 19	ENSP00000537181.1

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 756 AN: 152106 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00146 AC: 366 AN: 251450 AF XY: 0.00113

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000570 AC: 832 AN: 1459642 Hom.: 7 Cov.: 30 AF XY: 0.000512 AC XY: 372 AN XY: 726260

African (AFR) AF: 0.0201 AC: 671 AN: 33410

American (AMR) AF: 0.00110 AC: 49 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5744

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1109996

Other (OTH) AF: 0.000862 AC: 52 AN: 60330

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152224 Hom.: 3 Cov.: 32 AF XY: 0.00497 AC XY: 370 AN XY: 74408

African (AFR) AF: 0.0174 AC: 721 AN: 41540

American (AMR) AF: 0.00164 AC: 25 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00237 Hom.: 2

Bravo AF: 0.00558

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.6
DANN	Benign	0.59
PhyloP100		-1.5
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=297/3	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: rs704794; hg19: chr2-27719763;