rs4607517

Variant names:

• chr7-44196069-G-A
• rs4607517
• ENST00000476008.1:n.480+1622C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-44196069-G-A
• chr7-44196069-G-C

Variant summary

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

The ENST00000849947.1(ENSG00000310458):​n.67-1515G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 152,240 control chromosomes in the GnomAD database, including 1,706 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 0.14 (1706 hom., cov: 33)
• Consequence: ENSG00000310458 ENST00000849947.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.182
• Publications: 216 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

ENSG00000310458 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000849947.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000476008.1	TSL:5	n.480+1622C>T		intron	N/A
	ENSG00000310458	ENST00000849947.1		n.67-1515G>A		intron	N/A
	ENSG00000310458	ENST00000849948.1		n.65-1576G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22053 AN: 152122 Hom.: 1705 Cov.: 33

Gnomad AFR AF: 0.0857

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.176

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

GnomAD4 genome AF: 0.145 AC: 22053 AN: 152240 Hom.: 1706 Cov.: 33 AF XY: 0.143 AC XY: 10642 AN XY: 74438

African (AFR) AF: 0.0857 AC: 3562 AN: 41550

American (AMR) AF: 0.183 AC: 2806 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 593 AN: 3468

East Asian (EAS) AF: 0.188 AC: 973 AN: 5182

South Asian (SAS) AF: 0.139 AC: 668 AN: 4822

European-Finnish (FIN) AF: 0.109 AC: 1151 AN: 10602

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11618 AN: 68006

Other (OTH) AF: 0.174 AC: 367 AN: 2110

Alfa AF: 0.166 Hom.: 10487

Bravo AF: 0.151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		-0.18

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4607517; hg19: chr7-44235668;