rs7486100

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_013254.4(TBK1):c.978T>A(p.Ile326Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,572,000 control chromosomes in the GnomAD database, including 225,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 16495 hom., cov: 31)

Exomes 𝑓: 0.53 ( 208928 hom. )

Consequence

TBK1
NM_013254.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.13

Publications

32 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 12-64482007-T-A is Benign according to our data. Variant chr12-64482007-T-A is described in ClinVar as Benign. ClinVar VariationId is 403522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013254.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	NM_013254.4	MANE Select	c.978T>A	p.Ile326Ile	synonymous	Exon 8 of 21	NP_037386.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TBK1	ENST00000331710.10	TSL:1 MANE Select	c.978T>A	p.Ile326Ile	synonymous	Exon 8 of 21	ENSP00000329967.5
TBK1	ENST00000650790.1		c.978T>A	p.Ile326Ile	synonymous	Exon 8 of 21	ENSP00000498995.1
TBK1	ENST00000677641.1		c.978T>A	p.Ile326Ile	synonymous	Exon 8 of 21	ENSP00000504637.1

Frequencies

GnomAD3 genomes

AF:

0.437

AC:

66322

AN:

151878

Hom.:

16494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.200

Gnomad AMI

AF:

0.364

Gnomad AMR

AF:

0.457

Gnomad ASJ

AF:

0.413

Gnomad EAS

AF:

0.331

Gnomad SAS

AF:

0.376

Gnomad FIN

AF:

0.621

Gnomad MID

AF:

0.385

Gnomad NFE

AF:

0.562

Gnomad OTH

AF:

0.424

GnomAD2 exomes

AF:

0.477

AC:

107492

AN:

225502

AF XY:

0.482

show subpopulations

Gnomad AFR exome

AF:

0.201

Gnomad AMR exome

AF:

0.406

Gnomad ASJ exome

AF:

0.414

Gnomad EAS exome

AF:

0.326

Gnomad FIN exome

AF:

0.610

Gnomad NFE exome

AF:

0.555

Gnomad OTH exome

AF:

0.502

GnomAD4 exome

AF:

0.534

AC:

758964

AN:

1420006

Hom.:

208928

Cov.:

AF XY:

0.531

AC XY:

375105

AN XY:

706796

show subpopulations

African (AFR)

AF:

0.194

AC:

6115

AN:

31560

American (AMR)

AF:

0.408

AC:

16275

AN:

39882

Ashkenazi Jewish (ASJ)

AF:

0.417

AC:

10511

AN:

25198

East Asian (EAS)

AF:

0.369

AC:

13812

AN:

37470

South Asian (SAS)

AF:

0.390

AC:

31660

AN:

81092

European-Finnish (FIN)

AF:

0.601

AC:

31380

AN:

52174

Middle Eastern (MID)

AF:

0.388

AC:

2187

AN:

5642

European-Non Finnish (NFE)

AF:

0.568

AC:

617991

AN:

1088484

Other (OTH)

AF:

0.496

AC:

29033

AN:

58504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

14134

28267

42401

56534

70668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17092

34184

51276

68368

85460

<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:

0.436

AC:

66332

AN:

151994

Hom.:

16495

Cov.:

AF XY:

0.437

AC XY:

32484

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.200

AC:

8299

AN:

41472

American (AMR)

AF:

0.456

AC:

6960

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.413

AC:

1434

AN:

3468

East Asian (EAS)

AF:

0.332

AC:

1711

AN:

5160

South Asian (SAS)

AF:

0.377

AC:

1812

AN:

4812

European-Finnish (FIN)

AF:

0.621

AC:

6554

AN:

10560

Middle Eastern (MID)

AF:

0.377

AC:

110

AN:

292

European-Non Finnish (NFE)

AF:

0.562

AC:

38222

AN:

67960

Other (OTH)

AF:

0.426

AC:

899

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1717

3434

5151

6868

8585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<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:

0.509

Hom.:

6632

Bravo

AF:

0.414

Asia WGS

AF:

0.367

AC:

1282

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 73% of patients studied by a panel of primary immunodeficiencies. Number of patients: 69. Only high quality variants are reported.

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 02, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Glaucoma 1, open angle, P

Benign:1

Apr 22, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.6

(source)

DANN

Benign

0.63

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over