rs34002644

Variant names:

• chr3-120002133-T-A
• rs34002644
• NM_001146156.2:c.195A>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001146156.2(GSK3B):​c.195A>T​(p.Gly65Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,612,362 control chromosomes in the GnomAD database, including 1,708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (888 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (820 hom.)
• Consequence: GSK3B NM_001146156.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.153
• Publications: 6 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

ENSG00000288662 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 3-120002133-T-A is Benign according to our data. Variant chr3-120002133-T-A is described in ClinVar as [Benign]. Clinvar id is 1276817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.153 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSK3B	NM_001146156.2	c.195A>T	p.Gly65Gly	synonymous_variant	Exon 2 of 11	ENST00000264235.13	NP_001139628.1
GSK3B	NM_002093.4	c.195A>T	p.Gly65Gly	synonymous_variant	Exon 2 of 12		NP_002084.2
GSK3B	NM_001354596.2	c.195A>T	p.Gly65Gly	synonymous_variant	Exon 2 of 10		NP_001341525.1
GSK3B	XM_006713610.4	c.195A>T	p.Gly65Gly	synonymous_variant	Exon 2 of 11		XP_006713673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSK3B	ENST00000264235.13	c.195A>T	p.Gly65Gly	synonymous_variant	Exon 2 of 11	1	NM_001146156.2	ENSP00000264235.9

Frequencies

GnomAD3 genomes AF: 0.0601 AC: 9133 AN: 152066 Hom.: 883 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0398

GnomAD2 exomes AF: 0.0162 AC: 4042 AN: 250122 AF XY: 0.0121

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.00891

Gnomad ASJ exome AF: 0.000995

Gnomad EAS exome AF: 0.00229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000865

Gnomad OTH exome AF: 0.00689

GnomAD4 exome AF: 0.00720 AC: 10509 AN: 1460180 Hom.: 820 Cov.: 30 AF XY: 0.00636 AC XY: 4623 AN XY: 726416

African (AFR) AF: 0.209 AC: 6960 AN: 33240

American (AMR) AF: 0.0106 AC: 473 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.000881 AC: 23 AN: 26106

East Asian (EAS) AF: 0.0266 AC: 1052 AN: 39620

South Asian (SAS) AF: 0.00546 AC: 470 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5766

European-Non Finnish (NFE) AF: 0.000541 AC: 601 AN: 1111128

Other (OTH) AF: 0.0146 AC: 878 AN: 60320

GnomAD4 genome AF: 0.0602 AC: 9158 AN: 152182 Hom.: 888 Cov.: 32 AF XY: 0.0580 AC XY: 4313 AN XY: 74402

African (AFR) AF: 0.208 AC: 8636 AN: 41450

American (AMR) AF: 0.0204 AC: 312 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.0104 AC: 54 AN: 5184

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68028

Other (OTH) AF: 0.0394 AC: 83 AN: 2108

Alfa AF: 0.0182 Hom.: 77

Bravo AF: 0.0687

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000895

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.2
DANN	Benign	0.73
PhyloP100		0.15
PromoterAI		-0.015	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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: rs34002644; hg19: chr3-119720980;