dbSNP rs12639869: TBCK:n.*94G>T (chr4-106254947-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000467183.6(TBCK):n.*94G>T variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 164,326 control chromosomes in the GnomAD database, including 1,906 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 1703 hom., cov: 32)

Exomes 𝑓: 0.18 ( 203 hom. )

Consequence

TBCK
ENST00000467183.6 splice_region, non_coding_transcript_exon

Scores

Splicing: ADA: 0.000007043

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.728

Publications

8 publications found

Variant links:

Genes affected

TBCK (HGNC:28261): (TBC1 domain containing kinase) This gene encodes a protein that contains a protein kinase domain, a Rhodanase-like domain and the Tre-2/Bub2/Cdc16 (TBC) domain. The encoded protein is thought to play a role in actin organization, cell growth and cell proliferation by regulating the mammalian target of the rapamycin (mTOR) signaling pathway. This protein may also be involved in the transcriptional regulation of the components of the mTOR complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

TBCK Gene-Disease associations (from GenCC):

hypotonia, infantile, with psychomotor retardation and characteristic facies 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

TBCK links:

Genome browser will be placed here

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=-0.93).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCK	NM_001163435.3 link	c.456-2940G>T		intron_variant	Intron 5 of 25	ENST00000394708.7	NP_001156907.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCK	ENST00000394708.7 link	c.456-2940G>T		intron_variant	Intron 5 of 25	1	NM_001163435.3	ENSP00000378198.2

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21423

AN:

151338

Hom.:

1709

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0699

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.138

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.199

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.175

Gnomad OTH

AF:

0.128

GnomAD4 exome

AF:

0.176

AC:

2260

AN:

12872

Hom.:

203

Cov.:

AF XY:

0.179

AC XY:

1548

AN XY:

8636

show subpopulations

African (AFR)

AF:

0.0870

AC:

AN:

230

American (AMR)

AF:

0.121

AC:

AN:

330

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

AN:

598

East Asian (EAS)

AF:

0.194

AC:

AN:

222

South Asian (SAS)

AF:

0.229

AC:

463

AN:

2026

European-Finnish (FIN)

AF:

0.187

AC:

AN:

428

Middle Eastern (MID)

AF:

0.137

AC:

219

AN:

1596

European-Non Finnish (NFE)

AF:

0.182

AC:

1240

AN:

6806

Other (OTH)

AF:

0.145

AC:

AN:

636

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

179

269

358

448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.141

AC:

21418

AN:

151454

Hom.:

1703

Cov.:

AF XY:

0.143

AC XY:

10563

AN XY:

74022

show subpopulations

African (AFR)

AF:

0.0699

AC:

2892

AN:

41358

American (AMR)

AF:

0.113

AC:

1721

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

427

AN:

3466

East Asian (EAS)

AF:

0.138

AC:

714

AN:

5164

South Asian (SAS)

AF:

0.251

AC:

1207

AN:

4812

European-Finnish (FIN)

AF:

0.199

AC:

2052

AN:

10324

Middle Eastern (MID)

AF:

0.100

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.175

AC:

11871

AN:

67806

Other (OTH)

AF:

0.129

AC:

270

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

944

1887

2831

3774

4718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<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:

0.151

Hom.:

329

Bravo

AF:

0.130

Asia WGS

AF:

0.203

AC:

704

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

0.73

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000070

dbscSNV1_RF

Benign

0.0

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

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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