12-64497257-G-C
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_013254.4(TBK1):c.1957G>C(p.Glu653Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000186 in 1,571,566 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_013254.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBK1 | NM_013254.4 | c.1957G>C | p.Glu653Gln | missense_variant, splice_region_variant | 18/21 | ENST00000331710.10 | NP_037386.1 | |
TBK1 | XM_005268809.2 | c.1957G>C | p.Glu653Gln | missense_variant, splice_region_variant | 18/21 | XP_005268866.1 | ||
TBK1 | XM_005268810.2 | c.1957G>C | p.Glu653Gln | missense_variant, splice_region_variant | 18/21 | XP_005268867.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBK1 | ENST00000331710.10 | c.1957G>C | p.Glu653Gln | missense_variant, splice_region_variant | 18/21 | 1 | NM_013254.4 | ENSP00000329967.5 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000267 AC: 60AN: 224686Hom.: 0 AF XY: 0.000279 AC XY: 34AN XY: 121864
GnomAD4 exome AF: 0.000189 AC: 268AN: 1419396Hom.: 1 Cov.: 26 AF XY: 0.000196 AC XY: 138AN XY: 703240
GnomAD4 genome AF: 0.000158 AC: 24AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74332
ClinVar
Submissions by phenotype
Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 653 of the TBK1 protein (p.Glu653Gln). This variant is present in population databases (rs144370662, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (PMID: 28008748). ClinVar contains an entry for this variant (Variation ID: 580527). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
TBK1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 11, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at