chr7-44193746-A-T

Variant names:

• chr7-44193746-A-T
• rs735670
• ENST00000476008.1:n.480+3945T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000476008.1(GCK):​n.480+3945T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 152,174 control chromosomes in the GnomAD database, including 359 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.066 (359 hom., cov: 33)
• Consequence: GCK ENST00000476008.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.09
• Publications: 8 publications found

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]

GCK Gene-Disease associations (from GenCC):

• hyperinsulinism due to glucokinase deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000310458 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000476008.1	n.480+3945T>A		intron_variant	Intron 1 of 1	5
ENSG00000310458	ENST00000849947.1	n.66+37A>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0663 AC: 10075 AN: 152054 Hom.: 357 Cov.: 33

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0509

Gnomad ASJ AF: 0.0640

Gnomad EAS AF: 0.0854

Gnomad SAS AF: 0.0694

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0718

Gnomad OTH AF: 0.0717

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0663 AC: 10083 AN: 152174 Hom.: 359 Cov.: 33 AF XY: 0.0659 AC XY: 4900 AN XY: 74382

African (AFR) AF: 0.0579 AC: 2403 AN: 41510

American (AMR) AF: 0.0508 AC: 778 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0640 AC: 222 AN: 3470

East Asian (EAS) AF: 0.0851 AC: 439 AN: 5156

South Asian (SAS) AF: 0.0694 AC: 335 AN: 4824

European-Finnish (FIN) AF: 0.0699 AC: 739 AN: 10578

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0718 AC: 4881 AN: 68014

Other (OTH) AF: 0.0719 AC: 152 AN: 2114

Alfa AF: 0.0661 Hom.: 41

Bravo AF: 0.0645

Asia WGS AF: 0.0730 AC: 255 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.30
DANN	Benign	0.50
PhyloP100		-2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs735670; hg19: chr7-44233345;