rs62321379
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_001163435.3(TBCK):c.2060-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000476 in 1,596,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001163435.3 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBCK | NM_001163435.3 | c.2060-2A>G | splice_acceptor_variant | ENST00000394708.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBCK | ENST00000394708.7 | c.2060-2A>G | splice_acceptor_variant | 1 | NM_001163435.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000299 AC: 7AN: 234102Hom.: 0 AF XY: 0.0000158 AC XY: 2AN XY: 126856
GnomAD4 exome AF: 0.0000464 AC: 67AN: 1444478Hom.: 0 Cov.: 30 AF XY: 0.0000390 AC XY: 28AN XY: 717922
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74294
ClinVar
Submissions by phenotype
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | May 19, 2016 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Jun 20, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | TIDEX, University of British Columbia | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2022 | 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) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at