rs1555204731
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_013254.4(TBK1):βc.1387_1388delβ(p.Glu463SerfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000276 in 1,450,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000028 ( 0 hom. )
Consequence
TBK1
NM_013254.4 frameshift
NM_013254.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.43
Genes affected
TBK1 (HGNC:11584): (TANK binding kinase 1) The NF-kappa-B (NFKB) complex of proteins is inhibited by I-kappa-B (IKB) proteins, which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the IKB proteins by IKB kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation and nuclear translocation of the NFKB complex. The protein encoded by this gene is similar to IKB kinases and can mediate NFKB activation in response to certain growth factors. The protein is also an important kinase for antiviral innate immunity response. [provided by RefSeq, Sep 2021]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-64488531-CAG-C is Pathogenic according to our data. Variant chr12-64488531-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 542552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBK1 | NM_013254.4 | c.1387_1388del | p.Glu463SerfsTer13 | frameshift_variant | 12/21 | ENST00000331710.10 | |
TBK1 | XM_005268809.2 | c.1387_1388del | p.Glu463SerfsTer13 | frameshift_variant | 12/21 | ||
TBK1 | XM_005268810.2 | c.1387_1388del | p.Glu463SerfsTer13 | frameshift_variant | 12/21 | ||
TBK1 | XR_007063071.1 | n.1486_1487del | non_coding_transcript_exon_variant | 12/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBK1 | ENST00000331710.10 | c.1387_1388del | p.Glu463SerfsTer13 | frameshift_variant | 12/21 | 1 | NM_013254.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000415 AC: 1AN: 240820Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 130132
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GnomAD4 exome AF: 0.00000276 AC: 4AN: 1450644Hom.: 0 AF XY: 0.00000555 AC XY: 4AN XY: 720786
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
TBK1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 07, 2023 | The TBK1 c.1387_1388delGA variant is predicted to result in a frameshift and premature protein termination (p.Glu463Serfs*13). This variant was reported in an individual with amyotrophic lateral sclerosis (Cirulli et al. 2015. PubMed ID: 25700176, this study's case genotype counts for this variant can be found at http://alsdb.org/). This variant is reported in 0.00091% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in TBK1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 14, 2023 | This sequence change creates a premature translational stop signal (p.Glu463Serfs*13) in the TBK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBK1 are known to be pathogenic (PMID: 25803835, 26476236, 26581300). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 25700176). ClinVar contains an entry for this variant (Variation ID: 542552). For these reasons, this variant has been classified as Pathogenic. - |
Primary open angle glaucoma;C2750180:Herpes simplex encephalitis, susceptibility to, 1;C4225325:Frontotemporal dementia and/or amyotrophic lateral sclerosis 4;C4693542:Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Pathogenic and reported on 11-09-2017 by Lab or GTR ID 500031. 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. - |
Computational scores
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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