chr12-64455936-T-C

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.66T>C(p.Asn22Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 1,613,322 control chromosomes in the GnomAD database, including 1,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 116 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1616 hom. )

Consequence

TBK1
NM_013254.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.25

Publications

10 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=-0.5).

BP6

Variant 12-64455936-T-C is Benign according to our data. Variant chr12-64455936-T-C is described in ClinVar as [Benign]. Clinvar id is 475941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.25 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBK1	NM_013254.4 link	c.66T>C	p.Asn22Asn	synonymous_variant	Exon 2 of 21	ENST00000331710.10	NP_037386.1	Q9UHD2
TBK1	XM_005268809.2 link	c.66T>C	p.Asn22Asn	synonymous_variant	Exon 2 of 21		XP_005268866.1	Q9UHD2
TBK1	XM_005268810.2 link	c.66T>C	p.Asn22Asn	synonymous_variant	Exon 2 of 21		XP_005268867.1	Q9UHD2
TBK1	XR_007063071.1 link	n.165T>C		non_coding_transcript_exon_variant	Exon 2 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10 link	c.66T>C	p.Asn22Asn	synonymous_variant	Exon 2 of 21	1	NM_013254.4	ENSP00000329967.5		Q9UHD2

Frequencies

GnomAD3 genomes

AF:

0.0299

AC:

4551

AN:

152216

Hom.:

116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00827

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0169

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0294

Gnomad FIN

AF:

0.0412

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0469

Gnomad OTH

AF:

0.0205

GnomAD2 exomes

AF:

0.0324

AC:

8119

AN:

250762

AF XY:

0.0340

show subpopulations

Gnomad AFR exome

AF:

0.00683

Gnomad AMR exome

AF:

0.0165

Gnomad ASJ exome

AF:

0.0260

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0382

Gnomad NFE exome

AF:

0.0460

Gnomad OTH exome

AF:

0.0283

GnomAD4 exome

AF:

0.0445

AC:

64951

AN:

1460988

Hom.:

1616

Cov.:

AF XY:

0.0447

AC XY:

32480

AN XY:

726770

show subpopulations

African (AFR)

AF:

0.00613

AC:

205

AN:

33454

American (AMR)

AF:

0.0164

AC:

733

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.0267

AC:

696

AN:

26104

East Asian (EAS)

AF:

0.000126

AC:

AN:

39684

South Asian (SAS)

AF:

0.0338

AC:

2910

AN:

86132

European-Finnish (FIN)

AF:

0.0379

AC:

2026

AN:

53404

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0506

AC:

56270

AN:

1111464

Other (OTH)

AF:

0.0337

AC:

2035

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

2761

5523

8284

11046

13807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0299

AC:

4554

AN:

152334

Hom.:

116

Cov.:

AF XY:

0.0297

AC XY:

2211

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00825

AC:

343

AN:

41578

American (AMR)

AF:

0.0170

AC:

260

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.0296

AC:

143

AN:

4830

European-Finnish (FIN)

AF:

0.0412

AC:

437

AN:

10612

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0469

AC:

3192

AN:

68024

Other (OTH)

AF:

0.0203

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

238

476

715

953

1191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0428

Hom.:

279

Bravo

AF:

0.0266

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0434

EpiControl

AF:

0.0405

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 28, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glaucoma 1, open angle, P

Benign:1

Jul 20, 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

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

2.3

PromoterAI

0.033

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr12-64455936-T-C

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