rs2070971

Variant names:

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

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.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 (★★). The gene GCK is included in the ClinGen Criteria Specification Registry.

• 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
• Publications: 17 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, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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

Specifications for GCK are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -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 VariationId 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.

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.46-4521C>A		intron	N/A	NP_000153.1	Q53Y25
	GCK	NM_033507.3		c.48+1089C>A		intron	N/A	NP_277042.1	P35557-2
	GCK	NM_033508.3		c.42+89C>A		intron	N/A	NP_277043.1	P35557-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.46-4521C>A		intron	N/A	ENSP00000384247.3	P35557-1
	GCK	ENST00000395796.8	TSL:1	n.*43+89C>A		intron	N/A	ENSP00000379142.4	A0A8C8KJG0
	GCK	ENST00000671824.1		c.46-4521C>A		intron	N/A	ENSP00000500264.1	A0A5F9ZHE0

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

African (AFR) AF: 0.425 AC: 13799 AN: 32496

American (AMR) AF: 0.146 AC: 6191 AN: 42398

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 3800 AN: 24588

East Asian (EAS) AF: 0.287 AC: 11262 AN: 39194

South Asian (SAS) AF: 0.123 AC: 10121 AN: 82576

European-Finnish (FIN) AF: 0.191 AC: 10030 AN: 52564

Middle Eastern (MID) AF: 0.0895 AC: 504 AN: 5632

European-Non Finnish (NFE) AF: 0.136 AC: 147944 AN: 1091018

Other (OTH) AF: 0.154 AC: 9075 AN: 58880

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

African (AFR) AF: 0.416 AC: 17238 AN: 41392

American (AMR) AF: 0.149 AC: 2277 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 564 AN: 3470

East Asian (EAS) AF: 0.246 AC: 1267 AN: 5146

South Asian (SAS) AF: 0.132 AC: 636 AN: 4822

European-Finnish (FIN) AF: 0.200 AC: 2111 AN: 10580

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9518 AN: 67980

Other (OTH) AF: 0.181 AC: 382 AN: 2108

Alfa AF: 0.176 Hom.: 1145

Bravo AF: 0.232

Asia WGS AF: 0.189 AC: 657 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Maturity-onset diabetes of the young (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.59
PhyloP100		0.085
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2070971;

hg19: chr7-44197583;

COSMIC: COSV61754113;