chr7-44189037-G-C

Variant names:

• chr7-44189037-G-C
• rs13306391
• NM_000162.5:c.-84C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000162.5(GCK):​c.-84C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,552,338 control chromosomes in the GnomAD database, including 4,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (355 hom., cov: 32)
  • Exomes 𝑓: 0.071 (3710 hom.)
• Consequence: GCK NM_000162.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.563

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-44189037-G-C is Benign according to our data. Variant chr7-44189037-G-C is described in ClinVar as [Benign]. Clinvar id is 908803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-44189037-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.-84C>G		5_prime_UTR_variant	Exon 1 of 10	ENST00000403799.8	NP_000153.1
GCK	NM_001354800.1	c.-84C>G		5_prime_UTR_variant	Exon 1 of 11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.-84C>G		5_prime_UTR_variant	Exon 1 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.0657 AC: 9998 AN: 152116 Hom.: 353 Cov.: 32

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0509

Gnomad ASJ AF: 0.0641

Gnomad EAS AF: 0.0862

Gnomad SAS AF: 0.0691

Gnomad FIN AF: 0.0693

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0717

Gnomad OTH AF: 0.0712

GnomAD4 exome AF: 0.0708 AC: 99143 AN: 1400104 Hom.: 3710 Cov.: 23 AF XY: 0.0713 AC XY: 49740 AN XY: 697262

Gnomad4 AFR exome AF: 0.0546

Gnomad4 AMR exome AF: 0.0405

Gnomad4 ASJ exome AF: 0.0582

Gnomad4 EAS exome AF: 0.0764

Gnomad4 SAS exome AF: 0.0753

Gnomad4 FIN exome AF: 0.0774

Gnomad4 NFE exome AF: 0.0721

Gnomad4 OTH exome AF: 0.0671

GnomAD4 genome AF: 0.0657 AC: 10006 AN: 152234 Hom.: 355 Cov.: 32 AF XY: 0.0653 AC XY: 4858 AN XY: 74428

Gnomad4 AFR AF: 0.0561

Gnomad4 AMR AF: 0.0509

Gnomad4 ASJ AF: 0.0641

Gnomad4 EAS AF: 0.0860

Gnomad4 SAS AF: 0.0692

Gnomad4 FIN AF: 0.0693

Gnomad4 NFE AF: 0.0717

Gnomad4 OTH AF: 0.0714

Alfa AF: 0.0206 Hom.: 18

Bravo AF: 0.0640

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Transient Neonatal Diabetes, Recessive Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 mellitus in young Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs13306391 in MODY, yet. -

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Permanent neonatal diabetes mellitus Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.89
CADD	Benign	4.8
DANN	Benign	0.64

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: rs13306391; hg19: chr7-44228636; COSMIC: COSV67886206; COSMIC: COSV67886206;