12-64466994-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3PP5BS2

The NM_013254.4(TBK1):c.452C>T(p.Ser151Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000763 in 1,612,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

TBK1
NM_013254.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 6.05

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.776

PP5

Variant 12-64466994-C-T is Pathogenic according to our data. Variant chr12-64466994-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 266068.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBK1	NM_013254.4 link	c.452C>T	p.Ser151Phe	missense_variant	Exon 5 of 21	ENST00000331710.10	NP_037386.1	Q9UHD2
TBK1	XM_005268809.2 link	c.452C>T	p.Ser151Phe	missense_variant	Exon 5 of 21		XP_005268866.1	Q9UHD2
TBK1	XM_005268810.2 link	c.452C>T	p.Ser151Phe	missense_variant	Exon 5 of 21		XP_005268867.1	Q9UHD2
TBK1	XR_007063071.1 link	n.551C>T		non_coding_transcript_exon_variant	Exon 5 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10 link	c.452C>T	p.Ser151Phe	missense_variant	Exon 5 of 21	1	NM_013254.4	ENSP00000329967.5		Q9UHD2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

250376

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000835

AC:

122

AN:

1460424

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

726552

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Motor neuron disease

Pathogenic:1

Aug 31, 2016

Centre for Genomic and Experimental Medicine, University of Edinburgh

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

not specified

Uncertain:1

Jan 06, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TBK1 c.452C>T (p.Ser151Phe) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250376 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.452C>T has been reported in the literature in individuals affected with Amyotrophic lateral sclerosis, motor neuron disease, Dementia with Lewy bodies (Cirulli_2015, Black_2017, Orme_2020, Scaber_2023). These reports do not provide unequivocal conclusions about association of the variant with Autoinflammation with arthritis and vasculitis. At least one publication reports experimental evidence evaluating an impact on protein function and this variant affected protein function (Ye_2019). The following publications have been ascertained in the context of this evaluation (PMID: 28089114, 25700176, 25803835, 31996268, 37159497, 31748271). ClinVar contains an entry for this variant (Variation ID: 266068). Based on the evidence outlined above, the variant was classified as uncertain significance. -

TBK1-related disorder

Uncertain:1

May 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TBK1 c.452C>T variant is predicted to result in the amino acid substitution p.Ser151Phe. This variant has been reported in a patient with dementia with Lewy bodies and in a patient with motor neuron disease (Table S3 Orme et al. 2020. PubMed ID: 31996268; Table S4 Black. 2017. PubMed ID: 28089114). However, pathogenicity of the c.452C>T variant was not confirmed through additional studies. This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Uncertain:1

Jul 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 151 of the TBK1 protein (p.Ser151Phe). This variant is present in population databases (rs55824172, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of amyotrophic lateral sclerosis and/or TBK1-related conditions (PMID: 21447600, 28089114, 31996268; Invitae). ClinVar contains an entry for this variant (Variation ID: 266068). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TBK1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects TBK1 function (PMID: 31748271). This variant disrupts the p.Ser151 amino acid residue in TBK1. Other variant(s) that disrupt this residue have been observed in individuals with TBK1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4;C4693542:Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8;C5935634:Autoinflammation with arthritis and vasculitis

Uncertain:1

Sep 15, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.098

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.2

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.86

MVP

0.79

MPC

1.1

ClinPred

0.92

GERP RS

5.2

Varity_R

0.87

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over