rs2070971

Variant names:

• chr7-44157984-G-T
• rs2070971
• NM_000162.5:c.46-4521C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000162.5(GCK):​c.46-4521C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,581,344 control chromosomes in the GnomAD database, including 23,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4932 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18068 hom.)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0850

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-44157984-G-T is Benign according to our data. Variant chr7-44157984-G-T is described in ClinVar as [Benign]. Clinvar id is 683652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.46-4521C>A		intron_variant	Intron 1 of 9	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.48+1089C>A		intron_variant	Intron 1 of 9		NP_277042.1
GCK	NM_033508.3	c.42+89C>A		intron_variant	Intron 2 of 10		NP_277043.1
GCK	NM_001354800.1	c.46-4521C>A		intron_variant	Intron 1 of 10		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.46-4521C>A		intron_variant	Intron 1 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34067 AN: 151880 Hom.: 4918 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.182

GnomAD4 exome AF: 0.149 AC: 212726 AN: 1429346 Hom.: 18068 AF XY: 0.147 AC XY: 104088 AN XY: 707836

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.287

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.224 AC: 34117 AN: 151998 Hom.: 4932 Cov.: 32 AF XY: 0.224 AC XY: 16617 AN XY: 74290

Gnomad4 AFR AF: 0.416

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.246

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.181

Alfa AF: 0.175 Hom.: 924

Bravo AF: 0.232

Asia WGS AF: 0.189 AC: 657 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity onset diabetes mellitus in young Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs2070971 in MODY, yet. -

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.59

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: rs2070971; hg19: chr7-44197583; COSMIC: COSV61754113;