rs575822089

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001290768.2(TBCK):c.-242C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,510,172 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

TBCK
NM_001290768.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 2.90

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

BayesDel_addAF computational evidence supports a deleterious effect, 0.416

PP5

Variant 4-106262103-G-A is Pathogenic according to our data. Variant chr4-106262103-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 225235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-106262103-G-A is described in Lovd as [Pathogenic]. Variant chr4-106262103-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCK	NM_001163435.3 link	c.376C>T	p.Arg126*	stop_gained	Exon 4 of 26	ENST00000394708.7	NP_001156907.2	Q8TEA7-1A0A024RDH3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCK	ENST00000394708.7 link	c.376C>T	p.Arg126*	stop_gained	Exon 4 of 26	1	NM_001163435.3	ENSP00000378198.2		Q8TEA7-1

Frequencies

GnomAD3 genomes

AF:

0.000238

AC:

AN:

151396

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00198

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:

0.0000442

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000772

AC:

AN:

142542

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

75414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000279

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000995

GnomAD4 exome

AF:

0.0000604

AC:

AN:

1358660

Hom.:

Cov.:

AF XY:

0.0000567

AC XY:

AN XY:

670738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000702

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000465

Gnomad4 OTH exome

AF:

0.000178

GnomAD4 genome

AF:

0.000238

AC:

AN:

151512

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

74004

show subpopulations

Gnomad4 AFR

AF:

0.0000485

Gnomad4 AMR

AF:

0.00197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.0000889

Hom.:

Bravo

AF:

0.000782

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 3

Pathogenic:8Other:1

Jul 29, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PM3 -

May 19, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 08-19-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Oct 25, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TBCK c.376C>T (p.Arg126X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.7e-05 in 142542 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TBCK causing Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (7.7e-05 vs 0.0011). c.376C>T has been reported in the literature in multiple individuals, predominantly of Puerto Rican descent (in compound heterozygous or homozygous state) affected with Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (Chong_2016, Bhoj_2016, Ortiz-Gonzlez_2018). These data indicate that the variant is very likely to be associated with disease. Chong_2016 reports the variant perturbs the levels of both major TBCK protein isoforms in fibroblasts. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 17, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 15, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg126Ter variant in TBCK has been reported in at least 10 individuals with TBCK-related intellectual disability syndrome (PMID: 27040692, 27040691, 29283439, 31618753; DOI: 10.1055:s-0039-1684016), segregated with disease in 2 affected relatives from 2 families, and has been identified in 0.1% (53/47944) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs575822089). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 225235) and has been interpreted as pathogenic by many submitters. Of the many affected individuals, at least eight of those were homozygotes, which increases the likelihood that the p.Arg126Ter variant is pathogenic (Variation ID: 27040692, 27040691, 29283439). In vitro functional studies provide some evidence that the p.Arg126Ter variant may impact protein function (PMID: 27040692, 29283439, 34816123). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 126, which is predicted to lead to a truncated or absent protein. Loss of function of the TBCK gene is an established disease mechanism in autosomal recessive TBCK-related intellectual disability syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive TBCK-related intellectual disability syndrome. ACMG/AMP Criteria applied: PVS1, PM3_strong, PS3_moderate, PP1 (Richards 2015). -

Aug 26, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376C>T (p.Arg126Ter) variant identified in the TBCK gene results in the premature termination of the protein at amino acid 126/894 (coding exon 4/26). This is predicted to lead to the termination of the protein within the protein kinase domain and result in the absence of Rab-GAP TBC and RHOD domains. This variant is found with low frequency in gnomAD (13 heterozygotes, 0 homozygotes; allele frequency: 7.48e-5) suggesting it is not a common benign variant in the populations represented in this database. This variant is reported as Pathogenic/Likely Pathogenic in ClinVar (VarID:225235), and has been reported in more than 10 affected individuals in the literature [PMID:27040692; PMID:27040691; PMID:29283439; PMID:31618753] in both homozygosity [PMID:27040692; PMID:27040691; PMID:29283439] and in compound heterozygosity with a second pathogenic variant [PMID:27040691; PMID:29283439]. Functional studies suggest this variant leads to increased levels of autophagic flux. This variant was identifed in homozygosity in an individual submitted for clinical WGS. Given the deleterious nature of the homozygous c.376C>T (p.Arg126Ter) variant identified in this individual, its low frequency in population databases, and the observation in many affected individuals in the literature, it is reported here as Pathogenic. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Nov 15, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27040692, 27040691, 29283439, 30577886) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg126*) in the TBCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBCK are known to be pathogenic (PMID: 27040692, 30103036). This variant is present in population databases (rs575822089, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with TBCK-related severe infantile syndromic encephalopathy or TBCK-related intellectual disability and hypotonia syndrome (PMID: 27040691, 27040692). ClinVar contains an entry for this variant (Variation ID: 225235). For these reasons, this variant has been classified as Pathogenic. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Syndromic Infantile Encephalopathy

Pathogenic:1

Apr 07, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Inborn genetic diseases

Pathogenic:1

Oct 01, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376C>T (p.R126*) alteration, located in exon 4 (coding exon 3) of the TBCK gene, consists of a C to T substitution at nucleotide position 376. This changes the amino acid from a Arginine (R) to a stop codon at amino acid position 126. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.007% (13/173798) total alleles studied. This alteration has been described in the homozygous state and compound heterozygous with a second TBCK variant in multiple unrelated individuals, primarily of Puerto Rican descent (Bhoj, 2016; Chong, 2016; Ortiz-Gonzalez, 2018; Baker, 2019; Ziats, 2020). Additionally, we have identified this variant in the homozygous state via whole exome sequencing at Ambry Genetics in four patients with clinical features of TBCK-related neurodevelopmental disorders. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Benign

0.54

Vest4

0.17

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over