Genetic Variant NM_001146156.2:c.*3445C>T (chr3-119823343-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001146156.2(GSK3B):c.*3445C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 204,540 control chromosomes in the GnomAD database, including 6,742 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 4929 hom., cov: 32)

Exomes 𝑓: 0.24 ( 1813 hom. )

Consequence

GSK3B
NM_001146156.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.371

Publications

11 publications found

Variant links:

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

GSK3B links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GSK3B	NM_001146156.2 link	c.*3445C>T	3_prime_UTR_variant	Exon 11 of 11	ENST00000264235.13	NP_001139628.1	P49841-1Q6FI27
GSK3B	NM_002093.4 link	c.*3445C>T	3_prime_UTR_variant	Exon 12 of 12		NP_002084.2	P49841-2
GSK3B	NM_001354596.2 link	c.*3445C>T	3_prime_UTR_variant	Exon 10 of 10		NP_001341525.1
GSK3B	XM_006713610.4 link	c.*3445C>T	3_prime_UTR_variant	Exon 11 of 11		XP_006713673.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GSK3B	ENST00000264235.13 link	c.*3445C>T	3_prime_UTR_variant	Exon 11 of 11	1	NM_001146156.2	ENSP00000264235.9	P49841-1
GSK3B	ENST00000316626.6 link	c.*3445C>T	3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000324806.5	P49841-2
GSK3B	ENST00000678439.1 link	c.*3445C>T	3_prime_UTR_variant	Exon 12 of 12			ENSP00000503868.1	A0A7I2YQK0

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

36808

AN:

151942

Hom.:

4925

Cov.:

show subpopulations

Gnomad AFR

AF:

0.314

Gnomad AMI

AF:

0.0789

Gnomad AMR

AF:

0.203

Gnomad ASJ

AF:

0.217

Gnomad EAS

AF:

0.483

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.268

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.185

Gnomad OTH

AF:

0.226

GnomAD4 exome

AF:

0.242

AC:

12697

AN:

52478

Hom.:

1813

Cov.:

AF XY:

0.242

AC XY:

5912

AN XY:

24414

show subpopulations

African (AFR)

AF:

0.322

AC:

764

AN:

2374

American (AMR)

AF:

0.198

AC:

291

AN:

1470

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

742

AN:

3378

East Asian (EAS)

AF:

0.473

AC:

3869

AN:

8182

South Asian (SAS)

AF:

0.280

AC:

122

AN:

436

European-Finnish (FIN)

AF:

0.267

AC:

AN:

Middle Eastern (MID)

AF:

0.236

AC:

AN:

326

European-Non Finnish (NFE)

AF:

0.184

AC:

5857

AN:

31900

Other (OTH)

AF:

0.221

AC:

967

AN:

4382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

471

942

1412

1883

2354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.242

AC:

36857

AN:

152062

Hom.:

4929

Cov.:

AF XY:

0.246

AC XY:

18299

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.314

AC:

13010

AN:

41448

American (AMR)

AF:

0.204

AC:

3113

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.217

AC:

752

AN:

3470

East Asian (EAS)

AF:

0.483

AC:

2504

AN:

5180

South Asian (SAS)

AF:

0.295

AC:

1419

AN:

4818

European-Finnish (FIN)

AF:

0.268

AC:

2831

AN:

10572

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.185

AC:

12602

AN:

67976

Other (OTH)

AF:

0.226

AC:

477

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1370

2740

4111

5481

6851

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

380

760

1140

1520

1900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.212

Hom.:

1538

Bravo

AF:

0.240

Asia WGS

AF:

0.361

AC:

1254

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

7.8

(source)

DANN

Benign

0.81

PhyloP100

0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over