rs13306388

Positions:

• chr7-44144804-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000403799.8(GCK):​c.*332G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 411,720 control chromosomes in the GnomAD database, including 9,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3268 hom., cov: 33)
  • Exomes 𝑓: 0.21 (6699 hom.)
• Consequence: GCK ENST00000403799.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -1.23

Genes affected

GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-44144804-C-T is Benign according to our data. Variant chr7-44144804-C-T is described in ClinVar as [Benign]. Clinvar id is 360295.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.*332G>A		3_prime_UTR_variant	10/10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.*332G>A		3_prime_UTR_variant	10/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28637 AN: 152072 Hom.: 3267 Cov.: 33

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.0732

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.228

GnomAD4 exome AF: 0.211 AC: 54869 AN: 259532 Hom.: 6699 Cov.: 2 AF XY: 0.201 AC XY: 27491 AN XY: 136866

Gnomad4 AFR exome AF: 0.0504

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.237

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.0751

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.225

GnomAD4 genome AF: 0.188 AC: 28639 AN: 152188 Hom.: 3268 Cov.: 33 AF XY: 0.184 AC XY: 13682 AN XY: 74400

Gnomad4 AFR AF: 0.0524

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.229

Gnomad4 SAS AF: 0.0739

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.227

Alfa AF: 0.209 Hom.: 837

Bravo AF: 0.192

Asia WGS AF: 0.146 AC: 511 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

Transient Neonatal Diabetes, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Maturity-onset diabetes of the young type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Permanent neonatal diabetes mellitus Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hyperinsulinism due to glucokinase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs13306388; hg19: chr7-44184403;