NM_013254.4:c.1436_1437delTG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_013254.4(TBK1):​c.1436_1437delTG​(p.Val479GlufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,428 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TBK1
NM_013254.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.35

Publications

2 publications found
Variant links:
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]
TBK1 Gene-Disease associations (from GenCC):
  • frontotemporal dementia and/or amyotrophic lateral sclerosis 4
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
  • frontotemporal dementia with motor neuron disease
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
  • autoinflammation with arthritis and vasculitis
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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 12-64488579-CTG-C is Pathogenic according to our data. Variant chr12-64488579-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203436.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBK1NM_013254.4 linkc.1436_1437delTG p.Val479GlufsTer4 frameshift_variant Exon 12 of 21 ENST00000331710.10 NP_037386.1 Q9UHD2
TBK1XM_005268809.2 linkc.1436_1437delTG p.Val479GlufsTer4 frameshift_variant Exon 12 of 21 XP_005268866.1 Q9UHD2
TBK1XM_005268810.2 linkc.1436_1437delTG p.Val479GlufsTer4 frameshift_variant Exon 12 of 21 XP_005268867.1 Q9UHD2
TBK1XR_007063071.1 linkn.1535_1536delTG non_coding_transcript_exon_variant Exon 12 of 18

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBK1ENST00000331710.10 linkc.1436_1437delTG p.Val479GlufsTer4 frameshift_variant Exon 12 of 21 1 NM_013254.4 ENSP00000329967.5 Q9UHD2

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152138
Hom.:
0
Cov.:
32
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.93e-7
AC:
1
AN:
1443428
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
717280
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32662
American (AMR)
AF:
0.00
AC:
0
AN:
41950
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25674
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39208
South Asian (SAS)
AF:
0.00
AC:
0
AN:
81958
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52964
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5720
European-Non Finnish (NFE)
AF:
9.06e-7
AC:
1
AN:
1103594
Other (OTH)
AF:
0.00
AC:
0
AN:
59698
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152256
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74436
African (AFR)
AF:
0.00
AC:
0
AN:
41560
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68008
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 Pathogenic:2
May 01, 2015
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Mar 31, 2020
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.3
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs876657405; hg19: chr12-64882359; API