rs2971677

Variant names:

• chr7-44152661-C-A
• rs2971677
• NM_000162.5:c.209-236G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-44152661-C-A
• chr7-44152661-C-G

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.209-236G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 151,860 control chromosomes in the GnomAD database, including 4,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.22 (4474 hom., cov: 30)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.577

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=-0.86).
• BP6: Variant 7-44152661-C-A is Benign according to our data. Variant chr7-44152661-C-A is described in ClinVar as [Benign]. Clinvar id is 676857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.209-236G>T		intron_variant	Intron 2 of 9	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.212-236G>T		intron_variant	Intron 2 of 9		NP_277042.1
GCK	NM_033508.3	c.206-236G>T		intron_variant	Intron 3 of 10		NP_277043.1
GCK	NM_001354800.1	c.209-236G>T		intron_variant	Intron 2 of 10		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.209-236G>T		intron_variant	Intron 2 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33758 AN: 151748 Hom.: 4461 Cov.: 30

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.191

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

GnomAD4 genome AF: 0.223 AC: 33808 AN: 151860 Hom.: 4474 Cov.: 30 AF XY: 0.223 AC XY: 16534 AN XY: 74208

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.247

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.191

Alfa AF: 0.176 Hom.: 688

Bravo AF: 0.227

Asia WGS AF: 0.203 AC: 705 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 rs2971677 in MODY, yet. -

not provided Benign:1

Jun 20, 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	-0.86
CADD	Benign	1.6
DANN	Benign	0.73

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: rs2971677; hg19: chr7-44192260;