7-44149821-C-T

Variant names:

• chr7-44149821-C-T
• rs142817246
• NM_000162.5:c.618G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000162.5(GCK):​c.618G>A​(p.Thr206Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000639 in 1,614,130 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: GCK NM_000162.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -5.58
• Publications: 5 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: 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 7-44149821-C-T is Benign according to our data. Variant chr7-44149821-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.58 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00361 (550/152286) while in subpopulation AFR AF = 0.0123 (510/41550). AF 95% confidence interval is 0.0114. There are 3 homozygotes in GnomAd4. There are 249 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.618G>A	p.Thr206Thr	synonymous	Exon 6 of 10	NP_000153.1	Q53Y25
	GCK	NM_033507.3		c.621G>A	p.Thr207Thr	synonymous	Exon 6 of 10	NP_277042.1	P35557-2
	GCK	NM_033508.3		c.615G>A	p.Thr205Thr	synonymous	Exon 7 of 11	NP_277043.1	P35557-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.618G>A	p.Thr206Thr	synonymous	Exon 6 of 10	ENSP00000384247.3	P35557-1
	GCK	ENST00000395796.8	TSL:1	n.*616G>A		non_coding_transcript_exon	Exon 7 of 11	ENSP00000379142.4	A0A8C8KJG0
	GCK	ENST00000395796.8	TSL:1	n.*616G>A		3_prime_UTR	Exon 7 of 11	ENSP00000379142.4	A0A8C8KJG0

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 550 AN: 152168 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.000998 AC: 251 AN: 251444 AF XY: 0.000751

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000329 AC: 481 AN: 1461844 Hom.: 3 Cov.: 33 AF XY: 0.000308 AC XY: 224 AN XY: 727224

African (AFR) AF: 0.0105 AC: 351 AN: 33480

American (AMR) AF: 0.000961 AC: 43 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111996

Other (OTH) AF: 0.000811 AC: 49 AN: 60394

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152286 Hom.: 3 Cov.: 32 AF XY: 0.00334 AC XY: 249 AN XY: 74454

African (AFR) AF: 0.0123 AC: 510 AN: 41550

American (AMR) AF: 0.00190 AC: 29 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00414

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Maturity-onset diabetes of the young (2)
-	-	2	not provided (2)
-	-	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	-0.67
CADD	Benign	0.041
DANN	Benign	0.82
PhyloP100		-5.6
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs142817246; hg19: chr7-44189420;