3-119876414-T-G

Variant names:

• chr3-119876414-T-G
• NM_001146156.2:c.908A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001146156.2(GSK3B):​c.908A>C​(p.Lys303Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GSK3B NM_001146156.2 missense, splice_region
• Scores: Splicing: ADA: 0.9909
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

Genes affected

GSK3B (HGNC:4617): (glycogen synthase kinase 3 beta) The protein encoded by this gene is a serine-threonine kinase belonging to the glycogen synthase kinase subfamily. It is a negative regulator of glucose homeostasis and is involved in energy metabolism, inflammation, ER-stress, mitochondrial dysfunction, and apoptotic pathways. Defects in this gene have been associated with Parkinson disease and Alzheimer disease. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSK3B	NM_001146156.2	c.908A>C	p.Lys303Thr	missense_variant, splice_region_variant	Exon 8 of 11	ENST00000264235.13	NP_001139628.1
GSK3B	NM_002093.4	c.908A>C	p.Lys303Thr	missense_variant, splice_region_variant	Exon 8 of 12		NP_002084.2
GSK3B	NM_001354596.2	c.908A>C	p.Lys303Thr	missense_variant, splice_region_variant	Exon 8 of 10		NP_001341525.1
GSK3B	XM_006713610.4	c.908A>C	p.Lys303Thr	missense_variant, splice_region_variant	Exon 8 of 11		XP_006713673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSK3B	ENST00000264235.13	c.908A>C	p.Lys303Thr	missense_variant, splice_region_variant	Exon 8 of 11	1	NM_001146156.2	ENSP00000264235.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.26	N;N;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.4	D;N;.
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.042	D;D;.
Polyphen		0.86	P;P;.
Vest4		0.65
MutPred		0.56		Loss of methylation at K303 (P = 0.0039);Loss of methylation at K303 (P = 0.0039);Loss of methylation at K303 (P = 0.0039);
MVP		0.82
MPC		1.9
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.93
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.86
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-119595261;