rs781377703

Variant names:

• chr7-44189055-C-G
• rs781377703
• NM_000162.5:c.-102G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-44189055-C-G
• chr7-44189055-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000162.5(GCK):​c.-102G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,245,724 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: GCK NM_000162.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:4
• Conservation: PhyloP100: -0.612
• 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), Ambry Genetics, Genomics England PanelApp
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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.-102G>C		5_prime_UTR	Exon 1 of 10	NP_000153.1	Q53Y25
	GCK	NM_001354800.1		c.-102G>C		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.-102G>C		5_prime_UTR	Exon 1 of 10	ENSP00000384247.3	P35557-1
	GCK	ENST00000671824.1		c.-102G>C		5_prime_UTR	Exon 1 of 11	ENSP00000500264.1	A0A5F9ZHE0
	GCK	ENST00000673284.1		c.-102G>C		5_prime_UTR	Exon 1 of 11	ENSP00000499852.1	A0A5F9ZGW4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000265 AC: 33 AN: 1245724 Hom.: 0 Cov.: 18 AF XY: 0.0000144 AC XY: 9 AN XY: 624702

African (AFR) AF: 0.00 AC: 0 AN: 29320

American (AMR) AF: 0.00 AC: 0 AN: 38578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24340

East Asian (EAS) AF: 0.00 AC: 0 AN: 37008

South Asian (SAS) AF: 0.00 AC: 0 AN: 78830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4758

European-Non Finnish (NFE) AF: 0.0000341 AC: 32 AN: 937478

Other (OTH) AF: 0.0000188 AC: 1 AN: 53204

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hyperinsulinism due to glucokinase deficiency (1)
-	1	-	Maturity-onset diabetes of the young type 2 (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	-0.86
CADD	Benign	1.4
DANN	Benign	0.47
PhyloP100		-0.61
PromoterAI		-0.0082	Neutral

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: rs781377703; hg19: chr7-44228654;