NM_001146156.2:c.456G>A

Variant names:

• chr3-119923394-C-T
• rs17183890
• NM_001146156.2:c.456G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001146156.2(GSK3B):​c.456G>A​(p.Thr152Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000844 in 1,573,904 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (6 hom.)
• Consequence: GSK3B NM_001146156.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.669
• Publications: 5 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

ENSG00000297780 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 3-119923394-C-T is Benign according to our data. Variant chr3-119923394-C-T is described in ClinVar as Benign. ClinVar VariationId is 721176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.669 with no splicing effect.
• BS2: High AC in GnomAd4 at 615 AD gene.

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.456G>A	p.Thr152Thr	synonymous	Exon 4 of 11	NP_001139628.1	Q6FI27
	GSK3B	NM_002093.4		c.456G>A	p.Thr152Thr	synonymous	Exon 4 of 12	NP_002084.2
	GSK3B	NM_001354596.2		c.456G>A	p.Thr152Thr	synonymous	Exon 4 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.456G>A	p.Thr152Thr	synonymous	Exon 4 of 11	ENSP00000264235.9	P49841-1
	GSK3B	ENST00000316626.6	TSL:1	c.456G>A	p.Thr152Thr	synonymous	Exon 4 of 12	ENSP00000324806.5	P49841-2
	GSK3B	ENST00000678439.1		c.456G>A	p.Thr152Thr	synonymous	Exon 4 of 12	ENSP00000503868.1	A0A7I2YQK0

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 610 AN: 152014 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00120 AC: 294 AN: 245640 AF XY: 0.000897

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.000824

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.000501 AC: 713 AN: 1421772 Hom.: 6 Cov.: 25 AF XY: 0.000441 AC XY: 313 AN XY: 709308

African (AFR) AF: 0.0148 AC: 483 AN: 32584

American (AMR) AF: 0.00113 AC: 50 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.0000779 AC: 2 AN: 25686

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39346

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84680

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53178

Middle Eastern (MID) AF: 0.00159 AC: 9 AN: 5648

European-Non Finnish (NFE) AF: 0.0000938 AC: 101 AN: 1077318

Other (OTH) AF: 0.00107 AC: 63 AN: 59004

GnomAD4 genome AF: 0.00404 AC: 615 AN: 152132 Hom.: 2 Cov.: 32 AF XY: 0.00385 AC XY: 286 AN XY: 74376

African (AFR) AF: 0.0138 AC: 573 AN: 41498

American (AMR) AF: 0.000981 AC: 15 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 67996

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00176 Hom.: 0

Bravo AF: 0.00477

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.62
PhyloP100		-0.67
PromoterAI		-0.0014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

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: rs17183890; hg19: chr3-119642241; COSMIC: COSV99955201;