rs1554334478

Variant names:

• chr7-44145279-A-C
• NM_000162.5:c.1255T>G

Your query was ambiguous. Multiple possible variants found:

• chr7-44145279-A-C
• chr7-44145279-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2_Supporting PP2 PP3 PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1255T>G variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 419 (p.(Phe419Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.991, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.1256T>C (p.Phe419Ser), has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). This variant segregated with the disease with two informative meioses in a single family with diabetes, however, this does not meet the thresholds for PP1 set by the ClinGen MDEP VCEP (PMID:27236918, internal lab contributors). This variant was identified in an individual with diabetes, however, PP4 is unable to be evaluated due to incomplete clinical information. In summary, this variant meets the criteria to be classified as uncertain significance for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367397313/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense, splice_region
• Scores: Splicing: ADA: 0.8792
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 8.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.1255T>G	p.Phe419Val	missense_variant, splice_region_variant	Exon 10 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1255T>G	p.Phe419Val	missense_variant, splice_region_variant	Exon 10 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Uncertain:1

Jun 26, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1255T>G variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 419 (p.(Phe419Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.991, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.1256T>C (p.Phe419Ser), has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). This variant segregated with the disease with two informative meioses in a single family with diabetes, however, this does not meet the thresholds for PP1 set by the ClinGen MDEP VCEP (PMID: 27236918, internal lab contributors). This variant was identified in an individual with diabetes, however, PP4 is unable to be evaluated due to incomplete clinical information. In summary, this variant meets the criteria to be classified as uncertain significance for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	.;D;D;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;D;T;.;T;T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	.;.;M;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.6	.;D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.93
MutPred		0.98		.;.;Gain of MoRF binding (P = 0.073);.;.;.;
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-44184878;