chr12-64488477-CT-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_013254.4(TBK1):c.1341-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,507,074 control chromosomes in the GnomAD database, including 48 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 46 hom. )

Consequence

TBK1
NM_013254.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.179

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

TBK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 12-64488477-CT-C is Benign according to our data. Variant chr12-64488477-CT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475934.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 = 0.00602 (916/152120) while in subpopulation NFE AF = 0.00905 (615/67982). AF 95% confidence interval is 0.00845. There are 2 homozygotes in GnomAd4. There are 452 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TBK1	NM_013254.4 link	c.1341-3delT	splice_region_variant, intron_variant	Intron 11 of 20	ENST00000331710.10	NP_037386.1	Q9UHD2
TBK1	XM_005268809.2 link	c.1341-3delT	splice_region_variant, intron_variant	Intron 11 of 20		XP_005268866.1	Q9UHD2
TBK1	XM_005268810.2 link	c.1341-3delT	splice_region_variant, intron_variant	Intron 11 of 20		XP_005268867.1	Q9UHD2
TBK1	XR_007063071.1 link	n.1440-3delT	splice_region_variant, intron_variant	Intron 11 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10 link	c.1341-3delT		splice_region_variant, intron_variant	Intron 11 of 20	1	NM_013254.4	ENSP00000329967.5		Q9UHD2

Frequencies

GnomAD3 genomes

AF:

0.00603

AC:

917

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00905

Gnomad OTH

AF:

0.00576

GnomAD2 exomes

AF:

0.00697

AC:

1245

AN:

178590

AF XY:

0.00713

show subpopulations

Gnomad AFR exome

AF:

0.000928

Gnomad AMR exome

AF:

0.00290

Gnomad ASJ exome

AF:

0.00569

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.00906

Gnomad OTH exome

AF:

0.00500

GnomAD4 exome

AF:

0.00792

AC:

10730

AN:

1354954

Hom.:

Cov.:

AF XY:

0.00803

AC XY:

5408

AN XY:

673192

show subpopulations

African (AFR)

AF:

0.000970

AC:

AN:

28860

American (AMR)

AF:

0.00367

AC:

121

AN:

32944

Ashkenazi Jewish (ASJ)

AF:

0.00591

AC:

143

AN:

24202

East Asian (EAS)

AF:

0.0000554

AC:

AN:

36076

South Asian (SAS)

AF:

0.00599

AC:

433

AN:

72340

European-Finnish (FIN)

AF:

0.0113

AC:

573

AN:

50516

Middle Eastern (MID)

AF:

0.00773

AC:

AN:

4530

European-Non Finnish (NFE)

AF:

0.00858

AC:

9008

AN:

1049400

Other (OTH)

AF:

0.00690

AC:

387

AN:

56086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

503

1006

1508

2011

2514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

336

672

1008

1344

1680

<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:

0.00602

AC:

916

AN:

152120

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

452

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00157

AC:

AN:

41510

American (AMR)

AF:

0.00406

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00478

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0107

AC:

113

AN:

10566

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00905

AC:

615

AN:

67982

Other (OTH)

AF:

0.00475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00702

Hom.:

Bravo

AF:

0.00503

Asia WGS

AF:

0.00173

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 20, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TBK1: BP4, BS2 -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Benign:1

Jan 23, 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

PhyloP100

0.18

Mutation Taster

=100/0

polymorphism

(source)

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

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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