rs758988

Variant names:

• chr7-44181982-A-C
• rs758988
• NM_000162.5:c.45+6927T>G

Your query was ambiguous. Multiple possible variants found:

• chr7-44181982-A-C
• chr7-44181982-A-G
• chr7-44181982-A-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+6927T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 152,070 control chromosomes in the GnomAD database, including 55,725 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 0.86 (55725 hom., cov: 30)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890
• Publications: 6 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

LOC105375257 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.45+6927T>G		intron_variant	Intron 1 of 9	ENST00000403799.8	NP_000153.1
LOC105375257	XR_927222.3	n.592A>C		non_coding_transcript_exon_variant	Exon 1 of 3
GCK	NM_001354800.1	c.45+6927T>G		intron_variant	Intron 1 of 10		NP_001341729.1
LOC105375257	XR_927221.3	n.82-1320A>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.45+6927T>G		intron_variant	Intron 1 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.855 AC: 129975 AN: 151952 Hom.: 55681 Cov.: 30

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.854

Gnomad ASJ AF: 0.799

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.906

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.842

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

GnomAD4 genome AF: 0.855 AC: 130075 AN: 152070 Hom.: 55725 Cov.: 30 AF XY: 0.860 AC XY: 63977 AN XY: 74350

African (AFR) AF: 0.866 AC: 35912 AN: 41452

American (AMR) AF: 0.854 AC: 13053 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 2770 AN: 3468

East Asian (EAS) AF: 0.929 AC: 4802 AN: 5170

South Asian (SAS) AF: 0.857 AC: 4121 AN: 4810

European-Finnish (FIN) AF: 0.906 AC: 9598 AN: 10598

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57112 AN: 67972

Other (OTH) AF: 0.842 AC: 1779 AN: 2114

Alfa AF: 0.841 Hom.: 98227

Bravo AF: 0.850

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.1
DANN	Benign	0.79
PhyloP100		0.089
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: rs758988; hg19: chr7-44221581;