rs191795044

Variant names:

• chr7-44189406-G-A
• rs191795044
• NM_000162.5:c.-453C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_000162.5(GCK):​c.-453C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000539 in 244,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene GCK is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: GCK NM_000162.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -0.469
• Publications: 2 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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), Ambry Genetics, Genomics England PanelApp
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000512 (78/152312) while in subpopulation NFE AF = 0.00101 (69/68030). AF 95% confidence interval is 0.000821. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.-453C>T		5_prime_UTR	Exon 1 of 10	NP_000153.1	Q53Y25
	GCK	NM_001354800.1		c.-453C>T		5_prime_UTR	Exon 1 of 11	NP_001341729.1	A0A5F9ZGW4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.-453C>T		5_prime_UTR	Exon 1 of 10	ENSP00000384247.3	P35557-1
	GCK	ENST00000671824.1		c.-453C>T		5_prime_UTR	Exon 1 of 11	ENSP00000500264.1	A0A5F9ZHE0
	GCK	ENST00000673284.1		c.-453C>T		5_prime_UTR	Exon 1 of 11	ENSP00000499852.1	A0A5F9ZGW4

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000583 AC: 54 AN: 92658 Hom.: 0 Cov.: 0 AF XY: 0.000556 AC XY: 27 AN XY: 48576

African (AFR) AF: 0.00 AC: 0 AN: 3250

American (AMR) AF: 0.000444 AC: 2 AN: 4508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2276

East Asian (EAS) AF: 0.00 AC: 0 AN: 4848

South Asian (SAS) AF: 0.000370 AC: 5 AN: 13500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 326

European-Non Finnish (NFE) AF: 0.000811 AC: 45 AN: 55458

Other (OTH) AF: 0.000421 AC: 2 AN: 4752

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74486

African (AFR) AF: 0.0000963 AC: 4 AN: 41554

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000582 Hom.: 0

Bravo AF: 0.000555

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hyperinsulinism due to glucokinase deficiency (1)
-	-	1	Maturity-onset diabetes of the young (1)
-	1	-	Maturity-onset diabetes of the young type 2 (1)
-	1	-	not specified (1)
-	1	-	Permanent neonatal diabetes mellitus (1)
-	1	-	Transient Neonatal Diabetes, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.75
PhyloP100		-0.47
PromoterAI		-0.0019	Neutral
Mutation Taster		=300/0	polymorphism

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: rs191795044;

hg19: chr7-44229005;