rs741038

Variant names:

• chr7-44183880-G-A
• rs741038
• NM_000162.5:c.45+5029C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-44183880-G-A
• chr7-44183880-G-C
• chr7-44183880-G-T

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+5029C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 152,142 control chromosomes in the GnomAD database, including 37,622 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 0.70 (37622 hom., cov: 33)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.545
• Publications: 11 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.45+5029C>T		intron_variant	Intron 1 of 9	ENST00000403799.8	NP_000153.1
GCK	NM_001354800.1	c.45+5029C>T		intron_variant	Intron 1 of 10		NP_001341729.1
LOC105375257	XR_927221.3	n.241-104G>A		intron_variant	Intron 2 of 2
LOC105375257	XR_927222.3	n.919-104G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.45+5029C>T		intron_variant	Intron 1 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106776 AN: 152024 Hom.: 37586 Cov.: 33

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.665

Gnomad EAS AF: 0.743

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.686

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

GnomAD4 genome AF: 0.702 AC: 106866 AN: 152142 Hom.: 37622 Cov.: 33 AF XY: 0.705 AC XY: 52419 AN XY: 74390

African (AFR) AF: 0.755 AC: 31340 AN: 41506

American (AMR) AF: 0.703 AC: 10743 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 2309 AN: 3470

East Asian (EAS) AF: 0.744 AC: 3859 AN: 5190

South Asian (SAS) AF: 0.700 AC: 3373 AN: 4816

European-Finnish (FIN) AF: 0.687 AC: 7263 AN: 10572

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.674 AC: 45798 AN: 67982

Other (OTH) AF: 0.688 AC: 1454 AN: 2112

Alfa AF: 0.700 Hom.: 23645

Bravo AF: 0.705

Asia WGS AF: 0.716 AC: 2490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.54
PhyloP100		-0.55
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: rs741038; hg19: chr7-44223479;