rs145905497

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_013254.4(TBK1):c.964C>T(p.His322Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000398 in 1,599,724 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H322L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 2 hom. )

Consequence

TBK1
NM_013254.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.71

Publications

11 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

TBK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019347101).

BP6

Variant 12-64481993-C-T is Benign according to our data. Variant chr12-64481993-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252679.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000348 (53/152206) while in subpopulation SAS AF = 0.00145 (7/4820). AF 95% confidence interval is 0.000681. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TBK1	NM_013254.4 link	c.964C>T	p.His322Tyr	missense_variant	Exon 8 of 21	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2 link	c.964C>T	p.His322Tyr	missense_variant	Exon 8 of 21		XP_005268866.1
TBK1	XM_005268810.2 link	c.964C>T	p.His322Tyr	missense_variant	Exon 8 of 21		XP_005268867.1
TBK1	XR_007063071.1 link	n.1063C>T		non_coding_transcript_exon_variant	Exon 8 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10 link	c.964C>T	p.His322Tyr	missense_variant	Exon 8 of 21	1	NM_013254.4	ENSP00000329967.5

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000456

AC:

109

AN:

239296

AF XY:

0.000569

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000283

Gnomad OTH exome

AF:

0.000698

GnomAD4 exome

AF:

0.000403

AC:

583

AN:

1447518

Hom.:

Cov.:

AF XY:

0.000450

AC XY:

324

AN XY:

720358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32446

American (AMR)

AF:

0.0000469

AC:

AN:

42618

Ashkenazi Jewish (ASJ)

AF:

0.0000388

AC:

AN:

25768

East Asian (EAS)

AF:

0.00

AC:

AN:

38606

South Asian (SAS)

AF:

0.00222

AC:

187

AN:

84388

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52970

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.000321

AC:

355

AN:

1105250

Other (OTH)

AF:

0.000619

AC:

AN:

59746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

AF:

0.000348

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41532

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00145

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68004

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.000238

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000511

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TBK1-related disorder

Benign:1

Sep 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Benign:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.038

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.0

PhyloP100

5.7

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.34

Sift

Benign

0.23

Sift4G

Benign

1.0

Polyphen

0.98

Vest4

0.54

MVP

0.43

MPC

0.40

ClinPred

0.12

GERP RS

4.3

Varity_R

0.44

gMVP

0.63

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over