7-44186230-A-G

Variant names:

• chr7-44186230-A-G
• rs34807880
• NM_000162.5:c.45+2679T>C

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+2679T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0654 in 152,274 control chromosomes in the GnomAD database, including 349 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 0.065 (349 hom., cov: 33)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.974
• Publications: 4 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0786 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000162.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.45+2679T>C		intron	N/A	NP_000153.1
	GCK	NM_001354800.1		c.45+2679T>C		intron	N/A	NP_001341729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.45+2679T>C		intron	N/A	ENSP00000384247.3
	GCK	ENST00000671824.1		c.45+2679T>C		intron	N/A	ENSP00000500264.1
	GCK	ENST00000673284.1		c.45+2679T>C		intron	N/A	ENSP00000499852.1

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9955 AN: 152156 Hom.: 347 Cov.: 33

Gnomad AFR AF: 0.0550

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0639

Gnomad EAS AF: 0.0854

Gnomad SAS AF: 0.0691

Gnomad FIN AF: 0.0697

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0718

Gnomad OTH AF: 0.0712

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

GnomAD4 genome AF: 0.0654 AC: 9964 AN: 152274 Hom.: 349 Cov.: 33 AF XY: 0.0651 AC XY: 4848 AN XY: 74458

African (AFR) AF: 0.0550 AC: 2287 AN: 41550

American (AMR) AF: 0.0507 AC: 775 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 222 AN: 3472

East Asian (EAS) AF: 0.0852 AC: 441 AN: 5178

South Asian (SAS) AF: 0.0692 AC: 334 AN: 4830

European-Finnish (FIN) AF: 0.0697 AC: 739 AN: 10610

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

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

Other (OTH) AF: 0.0714 AC: 151 AN: 2114

Alfa AF: 0.0396 Hom.: 42

Bravo AF: 0.0637

Asia WGS AF: 0.0730 AC: 255 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.49
DANN	Benign	0.51
PhyloP100		-0.97
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: rs34807880; hg19: chr7-44225829;