rs34780996

Variant names:

• chr7-44183696-G-A
• rs34780996
• NM_000162.5:c.45+5213C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-44183696-G-A
• chr7-44183696-G-C
• chr7-44183696-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+5213C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 152,234 control chromosomes in the GnomAD database, including 285 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 0.055 (285 hom., cov: 32)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.725
• Publications: 1 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.45+5213C>T		intron_variant	Intron 1 of 9	ENST00000403799.8	NP_000153.1
GCK	NM_001354800.1	c.45+5213C>T		intron_variant	Intron 1 of 10		NP_001341729.1
LOC105375257	XR_927221.3	n.240+236G>A		intron_variant	Intron 2 of 2
LOC105375257	XR_927222.3	n.918+236G>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+5213C>T		intron_variant	Intron 1 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.0547 AC: 8325 AN: 152116 Hom.: 284 Cov.: 32

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0490

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.0856

Gnomad SAS AF: 0.0688

Gnomad FIN AF: 0.0694

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0715

Gnomad OTH AF: 0.0646

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

GnomAD4 genome AF: 0.0547 AC: 8328 AN: 152234 Hom.: 285 Cov.: 32 AF XY: 0.0546 AC XY: 4062 AN XY: 74440

African (AFR) AF: 0.0171 AC: 712 AN: 41546

American (AMR) AF: 0.0489 AC: 748 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3472

East Asian (EAS) AF: 0.0855 AC: 443 AN: 5184

South Asian (SAS) AF: 0.0688 AC: 332 AN: 4824

European-Finnish (FIN) AF: 0.0694 AC: 735 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0715 AC: 4866 AN: 68012

Other (OTH) AF: 0.0649 AC: 137 AN: 2112

Alfa AF: 0.0191 Hom.: 17

Bravo AF: 0.0517

Asia WGS AF: 0.0710 AC: 249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.010
DANN	Benign	0.44
PhyloP100		-0.72
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: rs34780996; hg19: chr7-44223295;