Submissions for variant NM_001163435.3(TBCK):c.2060-2A>G

gnomAD frequency: 0.00005  dbSNP: rs62321379

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
TIDEX, University of British Columbia	RCV000210871	SCV000586847	likely pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3		criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853381	SCV002228033	pathogenic	not provided	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 22 of the TBCK gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TBCK are known to be pathogenic (PMID: 27040692, 30103036). This variant is present in population databases (rs62321379, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with TBCK-related conditions (PMID: 27040691, 30542205). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225239). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001853381	SCV002552600	pathogenic	not provided	2022-07-22	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30542205, 27040691)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000210871	SCV005908000	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2025-01-13	criteria provided, single submitter	curation	The c.2060-2A>G variant in TBCK has been reported in at least three individuals with TBCK-related intellectual disability syndrome (PMID: 27040691, 30542205), and has been identified in 0.006% (71/1174210) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs62321379). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 225239) and has been interpreted as pathogenic by Invitae, OMIM, and GeneDx. Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the c.2060-2A>G variant is pathogenic (Variation ID: 225240; PMID: 27040691). This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. 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, PM2_supporting (Richards 2015).
OMIM	RCV000210871	SCV000267186	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2016-05-19	no assertion criteria provided	literature only
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000210871	SCV000599271	likely pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2016-06-20	no assertion criteria provided	clinical testing