chr3-119916153-G-C

Variant names:

• chr3-119916153-G-C
• rs201787969
• NM_001146156.2:c.499C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001146156.2(GSK3B):​c.499C>G​(p.Arg167Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GSK3B NM_001146156.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90
• Publications: 3 publications found

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]

GSK3B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146156.2. 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
	GSK3B	NM_001146156.2	MANE Select	c.499C>G	p.Arg167Gly	missense	Exon 5 of 11	NP_001139628.1	Q6FI27
	GSK3B	NM_002093.4		c.499C>G	p.Arg167Gly	missense	Exon 5 of 12	NP_002084.2
	GSK3B	NM_001354596.2		c.499C>G	p.Arg167Gly	missense	Exon 5 of 10	NP_001341525.1	A0A3B3ITW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSK3B	ENST00000264235.13	TSL:1 MANE Select	c.499C>G	p.Arg167Gly	missense	Exon 5 of 11	ENSP00000264235.9	P49841-1
	GSK3B	ENST00000316626.6	TSL:1	c.499C>G	p.Arg167Gly	missense	Exon 5 of 12	ENSP00000324806.5	P49841-2
	GSK3B	ENST00000678439.1		c.499C>G	p.Arg167Gly	missense	Exon 5 of 12	ENSP00000503868.1	A0A7I2YQK0

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 26

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.83		Loss of MoRF binding (P = 0.0893)
MVP		0.97
MPC		2.1
ClinPred		0.98	D
GERP RS		3.0
PromoterAI		0.0084	Neutral
Varity_R		0.97
gMVP		0.91
Mutation Taster		=6/94	disease causing

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: rs201787969; hg19: chr3-119635000;