chr7-44145044-G-T

Variant names:

• chr7-44145044-G-T
• rs557990162
• NM_000162.5:c.*92C>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_000162.5(GCK):​c.*92C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,553,958 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (39 hom.)
• Consequence: GCK NM_000162.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.27
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-44145044-G-T is Benign according to our data. Variant chr7-44145044-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360298.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 = 0.00374 (569/152256) while in subpopulation NFE AF = 0.00325 (221/67992). AF 95% confidence interval is 0.0029. There are 5 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.*92C>A		3_prime_UTR	Exon 10 of 10	NP_000153.1	Q53Y25
	GCK	NM_033507.3		c.*92C>A		3_prime_UTR	Exon 10 of 10	NP_277042.1	P35557-2
	GCK	NM_033508.3		c.*92C>A		3_prime_UTR	Exon 11 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.*92C>A		3_prime_UTR	Exon 10 of 10	ENSP00000384247.3	P35557-1
	GCK	ENST00000395796.8	TSL:1	n.*1488C>A		non_coding_transcript_exon	Exon 11 of 11	ENSP00000379142.4	A0A8C8KJG0
	GCK	ENST00000459642.1	TSL:1	n.870C>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 569 AN: 152138 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00389 AC: 5456 AN: 1401702 Hom.: 39 Cov.: 30 AF XY: 0.00380 AC XY: 2638 AN XY: 694708

African (AFR) AF: 0.000559 AC: 18 AN: 32202

American (AMR) AF: 0.000815 AC: 32 AN: 39266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25392

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36930

South Asian (SAS) AF: 0.000695 AC: 56 AN: 80520

European-Finnish (FIN) AF: 0.0302 AC: 1142 AN: 37854

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4094

European-Non Finnish (NFE) AF: 0.00368 AC: 3996 AN: 1087108

Other (OTH) AF: 0.00360 AC: 210 AN: 58336

GnomAD4 genome AF: 0.00374 AC: 569 AN: 152256 Hom.: 5 Cov.: 33 AF XY: 0.00465 AC XY: 346 AN XY: 74446

African (AFR) AF: 0.000577 AC: 24 AN: 41568

American (AMR) AF: 0.000850 AC: 13 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.0285 AC: 303 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00325 AC: 221 AN: 67992

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00176

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hyperinsulinism due to glucokinase deficiency (1)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	Maturity-onset diabetes of the young type 2 (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
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.51
DANN	Benign	0.78
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs557990162; hg19: chr7-44184643;