7-44145489-G-C

Variant names:

• chr7-44145489-G-C
• rs2908274
• NM_000162.5:c.1253+8C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000162.5(GCK):​c.1253+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GCK NM_000162.5 splice_region, intron
• Scores: Splicing: ADA: 0.0006345
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.451
• Publications: 0 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

ENSG00000300758 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.1253+8C>G		splice_region_variant, intron_variant	Intron 9 of 9	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1253+8C>G		splice_region_variant, intron_variant	Intron 9 of 9	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440376 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 714134

African (AFR) AF: 0.00 AC: 0 AN: 33142

American (AMR) AF: 0.00 AC: 0 AN: 42728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 38898

South Asian (SAS) AF: 0.00 AC: 0 AN: 84406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100596

Other (OTH) AF: 0.00 AC: 0 AN: 59466

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.8
DANN	Benign	0.82
PhyloP100		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00063
dbscSNV1_RF	Benign	0.012
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: rs2908274; hg19: chr7-44185088;