7-44149722-A-G

Variant names:

• chr7-44149722-A-G
• rs2268574
• NM_000162.5:c.679+38T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000162.5(GCK):​c.679+38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,592,566 control chromosomes in the GnomAD database, including 207,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (25486 hom., cov: 32)
  • Exomes 𝑓: 0.50 (181745 hom.)
• Consequence: GCK NM_000162.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.77
• Publications: 21 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

LOC105375258 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-44149722-A-G is Benign according to our data. Variant chr7-44149722-A-G is described in ClinVar as Benign. ClinVar VariationId is 673534.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.679+38T>C		intron_variant	Intron 6 of 9	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.679+38T>C		intron_variant	Intron 6 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86483 AN: 151798 Hom.: 25462 Cov.: 32

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.531 AC: 132823 AN: 250270 AF XY: 0.518

Gnomad AFR exome AF: 0.732

Gnomad AMR exome AF: 0.595

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.661

Gnomad FIN exome AF: 0.497

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.527

GnomAD4 exome AF: 0.499 AC: 718976 AN: 1440652 Hom.: 181745 Cov.: 26 AF XY: 0.496 AC XY: 356115 AN XY: 717960

African (AFR) AF: 0.735 AC: 24296 AN: 33078

American (AMR) AF: 0.593 AC: 26488 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 12958 AN: 26016

East Asian (EAS) AF: 0.631 AC: 24985 AN: 39578

South Asian (SAS) AF: 0.431 AC: 36946 AN: 85712

European-Finnish (FIN) AF: 0.500 AC: 26452 AN: 52934

Middle Eastern (MID) AF: 0.477 AC: 2732 AN: 5722

European-Non Finnish (NFE) AF: 0.488 AC: 534088 AN: 1093366

Other (OTH) AF: 0.504 AC: 30031 AN: 59608

GnomAD4 genome AF: 0.570 AC: 86554 AN: 151914 Hom.: 25486 Cov.: 32 AF XY: 0.569 AC XY: 42208 AN XY: 74226

African (AFR) AF: 0.729 AC: 30213 AN: 41456

American (AMR) AF: 0.567 AC: 8655 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1740 AN: 3462

East Asian (EAS) AF: 0.630 AC: 3240 AN: 5140

South Asian (SAS) AF: 0.436 AC: 2094 AN: 4808

European-Finnish (FIN) AF: 0.495 AC: 5225 AN: 10552

Middle Eastern (MID) AF: 0.490 AC: 143 AN: 292

European-Non Finnish (NFE) AF: 0.495 AC: 33615 AN: 67912

Other (OTH) AF: 0.557 AC: 1173 AN: 2106

Alfa AF: 0.541 Hom.: 4778

Bravo AF: 0.585

Asia WGS AF: 0.524 AC: 1822 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.90
CADD	Benign	0.19
DANN	Benign	0.26
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2268574; hg19: chr7-44189321; COSMIC: COSV60787932; COSMIC: COSV60787932;