rs2908290

Positions:

• chr7-44176538-G-A
• chr7-44176538-G-C
• chr7-44176538-G-T

Variant summary

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

The NM_000162.5(GCK):​c.45+12371C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 151,984 control chromosomes in the GnomAD database, including 14,012 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 0.42 (14012 hom., cov: 32)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18

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]

LOC105375257 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.45+12371C>T		intron_variant		ENST00000403799.8	NP_000153.1
LOC105375257	XR_927221.3	n.81+4083G>A		intron_variant, non_coding_transcript_variant
GCK	NM_001354800.1	c.45+12371C>T		intron_variant			NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.45+12371C>T		intron_variant		1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64319 AN: 151866 Hom.: 14000 Cov.: 32

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.397

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

GnomAD4 genome AF: 0.423 AC: 64356 AN: 151984 Hom.: 14012 Cov.: 32 AF XY: 0.425 AC XY: 31536 AN XY: 74274

Gnomad4 AFR AF: 0.534

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.371

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.374

Gnomad4 OTH AF: 0.394

Alfa AF: 0.375 Hom.: 23859

Bravo AF: 0.426

Asia WGS AF: 0.384 AC: 1334 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.5
DANN	Benign	0.63

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: rs2908290; hg19: chr7-44216137;