12-64497638-G-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_013254.4(TBK1):​c.1960-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 0)
Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

TBK1
NM_013254.4 intron

Scores

2
Splicing: ADA: 0.0003317
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.199

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBK1NM_013254.4 linkc.1960-10G>A intron_variant Intron 18 of 20 ENST00000331710.10 NP_037386.1 Q9UHD2
TBK1XM_005268809.2 linkc.1960-10G>A intron_variant Intron 18 of 20 XP_005268866.1 Q9UHD2
TBK1XM_005268810.2 linkc.1960-10G>A intron_variant Intron 18 of 20 XP_005268867.1 Q9UHD2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBK1ENST00000331710.10 linkc.1960-10G>A intron_variant Intron 18 of 20 1 NM_013254.4 ENSP00000329967.5 Q9UHD2

Frequencies

GnomAD3 genomes
Cov.:
0
GnomAD4 exome
AF:
0.00000595
AC:
3
AN:
504286
Hom.:
0
Cov.:
17
AF XY:
0.0000119
AC XY:
3
AN XY:
252988
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000803
AC:
1
AN:
12448
American (AMR)
AF:
0.00
AC:
0
AN:
9066
Ashkenazi Jewish (ASJ)
AF:
0.000101
AC:
1
AN:
9874
East Asian (EAS)
AF:
0.00
AC:
0
AN:
21308
South Asian (SAS)
AF:
0.0000569
AC:
1
AN:
17588
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
21826
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1808
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
386472
Other (OTH)
AF:
0.00
AC:
0
AN:
23896
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.292
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
Cov.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.70
CADD
Benign
6.7
DANN
Benign
0.73
PhyloP100
-0.20
PromoterAI
-0.0061
Neutral

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00033
dbscSNV1_RF
Benign
0.024
SpliceAI score (max)
0.0
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: rs371275822; hg19: chr12-64891418; API