rs2971676

Positions:

• chr7-44154883-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000162.5(GCK):​c.46-1420C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,220 control chromosomes in the GnomAD database, including 1,509 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 0.12 (1509 hom., cov: 33)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.799

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.46-1420C>T		intron_variant		ENST00000403799.8
GCK	NM_001354800.1	c.46-1420C>T		intron_variant
GCK	NM_033507.3	c.49-1420C>T		intron_variant
GCK	NM_033508.3	c.43-1420C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.46-1420C>T		intron_variant		1	NM_000162.5	P1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18406 AN: 152102 Hom.: 1505 Cov.: 33

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0662

Gnomad ASJ AF: 0.0983

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.0396

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0909

Gnomad OTH AF: 0.102

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

GnomAD4 genome AF: 0.121 AC: 18421 AN: 152220 Hom.: 1509 Cov.: 33 AF XY: 0.119 AC XY: 8826 AN XY: 74430

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.0661

Gnomad4 ASJ AF: 0.0983

Gnomad4 EAS AF: 0.0231

Gnomad4 SAS AF: 0.0394

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0909

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0951 Hom.: 459

Bravo AF: 0.123

Asia WGS AF: 0.0380 AC: 133 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.9
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs2971676; hg19: chr7-44194482;