rs1554335616

Variant names:

• chr7-44151075-G-A
• NM_000162.5:c.364C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-44151075-G-A
• chr7-44151075-G-C
• chr7-44151075-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_Supporting PP2 PP3 PS4_Moderate PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.364C>T variant in the glucokinase gene, GCK, causes an amino acid change of leucine to phenylalanine at codon 122 (p.(Leu122Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.954, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs: 29927023, 31905448, internal lab contributors). However, PP4 is unable to be evaluated due to insufficient clinical information. This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 3 families (PP1_Strong; PMID:31905448, internal lab contributors). In summary, c.364C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP1_Strong, PS4_Moderate, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367402230/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GCK NM_000162.5 missense, splice_region
• Scores: Splicing: ADA: 0.9955
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 5.88

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 Likely_pathogenic. Variant got 9 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.364C>T	p.Leu122Phe	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.367C>T	p.Leu123Phe	missense_variant, splice_region_variant	Exon 4 of 10		NP_277042.1
GCK	NM_033508.3	c.361C>T	p.Leu121Phe	missense_variant, splice_region_variant	Exon 5 of 11		NP_277043.1
GCK	NM_001354800.1	c.364C>T	p.Leu122Phe	missense_variant, splice_region_variant	Exon 4 of 11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.364C>T	p.Leu122Phe	missense_variant, splice_region_variant	Exon 4 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461602 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Aug 01, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.364C>T variant in the glucokinase gene, GCK, causes an amino acid change of leucine to phenylalanine at codon 122 (p.(Leu122Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.954, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMIDs: 29927023, 31905448, internal lab contributors). However, PP4 is unable to be evaluated due to insufficient clinical information. This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 3 families (PP1_Strong; PMID: 31905448, internal lab contributors). In summary, c.364C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP1_Strong, PS4_Moderate, PP2, PP3, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;M;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	.;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.89
MutPred		0.95		.;Loss of stability (P = 0.1654);.;.;
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
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: chr7-44190674;