7-44182405-A-T

Variant names:

• chr7-44182405-A-T
• rs1076439
• NM_000162.5:c.45+6504T>A

Variant summary

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

The NM_000162.5(GCK):​c.45+6504T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 151,562 control chromosomes in the GnomAD database, including 20,702 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 0.52 (20702 hom., cov: 32)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• Publications: 0 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

ENSG00000307930 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.45+6504T>A		intron_variant	Intron 1 of 9	ENST00000403799.8	NP_000153.1
GCK	NM_001354800.1	c.45+6504T>A		intron_variant	Intron 1 of 10		NP_001341729.1
LOC105375257	XR_927221.3	n.82-897A>T		intron_variant	Intron 1 of 2
LOC105375257	XR_927222.3	n.759+256A>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.45+6504T>A		intron_variant	Intron 1 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78622 AN: 151442 Hom.: 20674 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.501

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

GnomAD4 genome AF: 0.519 AC: 78695 AN: 151562 Hom.: 20702 Cov.: 32 AF XY: 0.523 AC XY: 38689 AN XY: 74026

African (AFR) AF: 0.457 AC: 18873 AN: 41324

American (AMR) AF: 0.512 AC: 7810 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1841 AN: 3460

East Asian (EAS) AF: 0.378 AC: 1947 AN: 5146

South Asian (SAS) AF: 0.601 AC: 2894 AN: 4812

European-Finnish (FIN) AF: 0.603 AC: 6312 AN: 10464

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37411 AN: 67800

Other (OTH) AF: 0.505 AC: 1064 AN: 2108

Alfa AF: 0.541 Hom.: 2825

Bravo AF: 0.507

Asia WGS AF: 0.521 AC: 1813 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.4
DANN	Benign	0.50
PhyloP100		1.1
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: rs1076439; hg19: chr7-44222004;