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. The variant received -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
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000162.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.209-236G>T		intron	N/A	NP_000153.1
	GCK	NM_033507.3		c.212-236G>T		intron	N/A	NP_277042.1
	GCK	NM_033508.3		c.206-236G>T		intron	N/A	NP_277043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.209-236G>T		intron	N/A	ENSP00000384247.3
	GCK	ENST00000395796.8	TSL:1	n.*207-236G>T		intron	N/A	ENSP00000379142.4
	GCK	ENST00000671824.1		c.209-236G>T		intron	N/A	ENSP00000500264.1

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

African (AFR) AF: 0.373 AC: 15416 AN: 41384

American (AMR) AF: 0.159 AC: 2430 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 594 AN: 3472

East Asian (EAS) AF: 0.247 AC: 1272 AN: 5144

South Asian (SAS) AF: 0.165 AC: 791 AN: 4802

European-Finnish (FIN) AF: 0.204 AC: 2151 AN: 10542

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10616 AN: 67944

Other (OTH) AF: 0.191 AC: 403 AN: 2106

Alfa AF: 0.183 Hom.: 1246

Bravo AF: 0.227

Asia WGS AF: 0.203 AC: 705 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.73
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2971677; hg19: chr7-44192260;