rs55714218

Variant names:

• chr7-44144376-TG-T
• rs55714218
• ENST00000395796.8:n.*2155delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000395796.8(GCK):​n.*2155delC variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (11659 hom., cov: 0)
  • Exomes 𝑓: 0.14 (3 hom.)
• Consequence: GCK ENST00000395796.8 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.01
• Publications: 6 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 7-44144376-TG-T is Benign according to our data. Variant chr7-44144376-TG-T is described in ClinVar as Benign. ClinVar VariationId is 360286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395796.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	NM_000162.5	MANE Select	c.*759delC		3_prime_UTR	Exon 10 of 10	NP_000153.1
	GCK	NM_033507.3		c.*759delC		3_prime_UTR	Exon 10 of 10	NP_277042.1
	GCK	NM_033508.3		c.*759delC		3_prime_UTR	Exon 11 of 11	NP_277043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000395796.8	TSL:1	n.*2155delC		non_coding_transcript_exon	Exon 11 of 11	ENSP00000379142.4
	GCK	ENST00000459642.1	TSL:1	n.1537delC		non_coding_transcript_exon	Exon 2 of 2
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.*759delC		3_prime_UTR	Exon 10 of 10	ENSP00000384247.3

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50716 AN: 152070 Hom.: 11624 Cov.: 0

Gnomad AFR AF: 0.653

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.140 AC: 19 AN: 136 Hom.: 3 Cov.: 0 AF XY: 0.167 AC XY: 11 AN XY: 66

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.188 AC: 3 AN: 16

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.111 AC: 12 AN: 108

Other (OTH) AF: 0.300 AC: 3 AN: 10

GnomAD4 genome AF: 0.334 AC: 50794 AN: 152188 Hom.: 11659 Cov.: 0 AF XY: 0.335 AC XY: 24942 AN XY: 74418

African (AFR) AF: 0.653 AC: 27087 AN: 41496

American (AMR) AF: 0.282 AC: 4309 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 588 AN: 3470

East Asian (EAS) AF: 0.383 AC: 1983 AN: 5172

South Asian (SAS) AF: 0.298 AC: 1442 AN: 4832

European-Finnish (FIN) AF: 0.234 AC: 2479 AN: 10606

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12150 AN: 67996

Other (OTH) AF: 0.278 AC: 587 AN: 2112

Alfa AF: 0.0466 Hom.: 188

Bravo AF: 0.351

Asia WGS AF: 0.331 AC: 1149 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hyperinsulinism, Dominant (1)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	not provided (1)
-	-	1	Permanent neonatal diabetes mellitus (1)
-	-	1	Transient Neonatal Diabetes, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
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

Other links and lift over

dbSNP: rs55714218; hg19: chr7-44183975; COSMIC: COSV56267447; COSMIC: COSV56267447;