rs575822089
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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
NM_001290768.2 5_prime_UTR_premature_start_codon_gain
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 2.90
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]
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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/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TBCK | NM_001163435.3 | c.376C>T | p.Arg126* | stop_gained | 4/26 | ENST00000394708.7 | NP_001156907.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.000238 AC: 36AN: 151396Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000772 AC: 11AN: 142542Hom.: 0 AF XY: 0.0000663 AC XY: 5AN XY: 75414
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GnomAD4 exome AF: 0.0000604 AC: 82AN: 1358660Hom.: 0 Cov.: 24 AF XY: 0.0000567 AC XY: 38AN XY: 670738
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GnomAD4 genome 0.000238 AC: 36AN: 151512Hom.: 0 Cov.: 32 AF XY: 0.000243 AC XY: 18AN XY: 74004
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 Pathogenic:7Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 25, 2019 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jul 29, 2022 | PVS1, PM2, PM3 - |
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Aug 07, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 19, 2016 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 17, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Aug 26, 2021 | 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. - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 2021 | 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) - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Syndromic Infantile Encephalopathy Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Apr 07, 2016 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 01, 2021 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at