chr12-64488537-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013254.4(TBK1):c.1391T>C(p.Val464Ala) variant causes a missense change. The variant allele was found at a frequency of 0.019 in 1,604,966 control chromosomes in the GnomAD database, including 317 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 22 hom., cov: 32)

Exomes 𝑓: 0.020 ( 295 hom. )

Consequence

TBK1
NM_013254.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 6.58

Publications

18 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044326484).

BP6

Variant 12-64488537-T-C is Benign according to our data. Variant chr12-64488537-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0141 (2141/152280) while in subpopulation NFE AF = 0.0223 (1519/68030). AF 95% confidence interval is 0.0214. There are 22 homozygotes in GnomAd4. There are 1029 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TBK1	NM_013254.4 link	c.1391T>C	p.Val464Ala	missense_variant	Exon 12 of 21	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2 link	c.1391T>C	p.Val464Ala	missense_variant	Exon 12 of 21		XP_005268866.1
TBK1	XM_005268810.2 link	c.1391T>C	p.Val464Ala	missense_variant	Exon 12 of 21		XP_005268867.1
TBK1	XR_007063071.1 link	n.1490T>C		non_coding_transcript_exon_variant	Exon 12 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10 link	c.1391T>C	p.Val464Ala	missense_variant	Exon 12 of 21	1	NM_013254.4	ENSP00000329967.5

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2140

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00323

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0223

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.0135

AC:

3268

AN:

242322

AF XY:

0.0136

show subpopulations

Gnomad AFR exome

AF:

0.00379

Gnomad AMR exome

AF:

0.00335

Gnomad ASJ exome

AF:

0.00901

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0249

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.0195

AC:

28337

AN:

1452686

Hom.:

295

Cov.:

AF XY:

0.0189

AC XY:

13627

AN XY:

721956

show subpopulations

African (AFR)

AF:

0.00362

AC:

120

AN:

33130

American (AMR)

AF:

0.00387

AC:

167

AN:

43204

Ashkenazi Jewish (ASJ)

AF:

0.0105

AC:

273

AN:

25882

East Asian (EAS)

AF:

0.00

AC:

AN:

39446

South Asian (SAS)

AF:

0.00686

AC:

571

AN:

83284

European-Finnish (FIN)

AF:

0.0242

AC:

1286

AN:

53210

Middle Eastern (MID)

AF:

0.00419

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0225

AC:

24920

AN:

1108712

Other (OTH)

AF:

0.0162

AC:

976

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

1277

2553

3830

5106

6383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

932

1864

2796

3728

4660

<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:

0.0141

AC:

2141

AN:

152280

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1029

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00322

AC:

134

AN:

41570

American (AMR)

AF:

0.00635

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00519

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0271

AC:

287

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0223

AC:

1519

AN:

68030

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

106

212

319

425

531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0164

Hom.:

Bravo

AF:

0.0123

TwinsUK

AF:

0.0216

AC:

ALSPAC

AF:

0.0241

AC:

ESP6500AA

AF:

0.00455

AC:

ESP6500EA

AF:

0.0203

AC:

175

ExAC

AF:

0.0132

AC:

1597

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0168

EpiControl

AF:

0.0152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 13, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TBK1: BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Glaucoma 1, open angle, P

Benign:2

Mar 06, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 21, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.076

Eigen

Benign

0.077

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.63

PhyloP100

6.6

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.31

REVEL

Benign

0.11

Sift

Benign

0.33

Sift4G

Benign

0.70

Vest4

0.17

ClinPred

0.016

GERP RS

5.3

Varity_R

0.26

gMVP

0.62

Mutation Taster

=79/21

polymorphism (auto)

(source)

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

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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