7-44146445-C-T

Variant names:

• chr7-44146445-C-T
• rs150914617
• NM_000162.5:c.1019+18G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033507.3(GCK):​c.1022+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,600,426 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (19 hom.)
• Consequence: GCK NM_033507.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.922
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-44146445-C-T is Benign according to our data. Variant chr7-44146445-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00309 (471/152286) while in subpopulation NFE AF = 0.00547 (372/68012). AF 95% confidence interval is 0.00501. There are 2 homozygotes in GnomAd4. There are 213 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033507.3. 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.1019+18G>A		intron	N/A	NP_000153.1
	GCK	NM_033507.3		c.1022+18G>A		intron	N/A	NP_277042.1
	GCK	NM_033508.3		c.1016+18G>A		intron	N/A	NP_277043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCK	ENST00000403799.8	TSL:1 MANE Select	c.1019+18G>A		intron	N/A	ENSP00000384247.3
	GCK	ENST00000395796.8	TSL:1	n.*1017+18G>A		intron	N/A	ENSP00000379142.4
	GCK	ENST00000671824.1		c.1082+18G>A		intron	N/A	ENSP00000500264.1

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152168 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00547

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00315 AC: 752 AN: 238614 AF XY: 0.00308

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00503

Gnomad NFE exome AF: 0.00517

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00412 AC: 5966 AN: 1448140 Hom.: 19 Cov.: 33 AF XY: 0.00403 AC XY: 2909 AN XY: 720946

African (AFR) AF: 0.000658 AC: 22 AN: 33430

American (AMR) AF: 0.00255 AC: 114 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86178

European-Finnish (FIN) AF: 0.00450 AC: 184 AN: 40934

Middle Eastern (MID) AF: 0.000971 AC: 5 AN: 5148

European-Non Finnish (NFE) AF: 0.00490 AC: 5452 AN: 1111750

Other (OTH) AF: 0.00282 AC: 170 AN: 60220

GnomAD4 genome AF: 0.00309 AC: 471 AN: 152286 Hom.: 2 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74464

African (AFR) AF: 0.000746 AC: 31 AN: 41560

American (AMR) AF: 0.00183 AC: 28 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00547 AC: 372 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00323 Hom.: 1

Bravo AF: 0.00275

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinism due to glucokinase deficiency;C5393570:Permanent neonatal diabetes mellitus 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.1
DANN	Benign	0.88
PhyloP100		-0.92
PromoterAI		-0.019	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs150914617; hg19: chr7-44186044;