rs1554334579

Variant names:

• chr7-44145577-G-T
• rs1554334579
• NM_000162.5:c.1173C>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_000162.5(GCK):​c.1173C>A​(p.Asn391Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Likely pathogenic/Likely risk allele criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.10
• 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: 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 33 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000162.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 274 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.069 (below the threshold of 3.09). Trascript score misZ: 2.7821 (below the threshold of 3.09). GenCC associations: The gene is linked to transient neonatal diabetes mellitus, monogenic diabetes, permanent neonatal diabetes mellitus 1, diabetes mellitus, noninsulin-dependent, maturity-onset diabetes of the young type 2, hyperinsulinism due to glucokinase deficiency, permanent neonatal diabetes mellitus, maturity-onset diabetes of the young.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753
• PP5: Variant 7-44145577-G-T is Pathogenic according to our data. Variant chr7-44145577-G-T is described in ClinVar as Likely_pathogenic/Likely_risk_allele. ClinVar VariationId is 435299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.1173C>A	p.Asn391Lys	missense_variant	Exon 9 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1173C>A	p.Asn391Lys	missense_variant	Exon 9 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450608 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721238

African (AFR) AF: 0.00 AC: 0 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 43668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39112

South Asian (SAS) AF: 0.00 AC: 0 AN: 85216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108360

Other (OTH) AF: 0.00 AC: 0 AN: 59944

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic/Likely risk allele

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Pathogenic:1

Feb 15, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Pathogenic:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely risk allele

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1554334579 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;T;D;.;.;.
Eigen	Benign	0.023
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;T;T;.;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	0.96	.;.;L;.;.;.
PhyloP100		4.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	.;N;N;N;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.11	.;T;D;D;D;D
Sift4G	Benign	0.22	T;D;T;T;T;T
Polyphen		1.0	D;.;D;D;P;P
Vest4		0.77
MutPred		0.56		.;.;Gain of MoRF binding (P = 0.0243);.;.;.;
MVP		0.95
MPC		2.3
ClinPred		0.91	D
GERP RS		3.8
Varity_R		0.61
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs1554334579; hg19: chr7-44185176;