chr12-64497638-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_013254.4(TBK1):c.1960-10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 0 hom., cov: 0)

Exomes 𝑓: 0.014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TBK1
NM_013254.4 intron

Scores

Splicing: ADA: 0.0007784

Clinical Significance

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

Conservation

PhyloP100: -0.199

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 12-64497638-G-T is Benign according to our data. Variant chr12-64497638-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 475937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TBK1	NM_013254.4 link	c.1960-10G>T	intron_variant	Intron 18 of 20	ENST00000331710.10	NP_037386.1	Q9UHD2
TBK1	XM_005268809.2 link	c.1960-10G>T	intron_variant	Intron 18 of 20		XP_005268866.1	Q9UHD2
TBK1	XM_005268810.2 link	c.1960-10G>T	intron_variant	Intron 18 of 20		XP_005268867.1	Q9UHD2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10 link	c.1960-10G>T		intron_variant	Intron 18 of 20	1	NM_013254.4	ENSP00000329967.5		Q9UHD2

Frequencies

GnomAD3 genomes

AF:

0.0401

AC:

1514

AN:

37732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0312

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0373

Gnomad ASJ

AF:

0.0526

Gnomad EAS

AF:

0.0170

Gnomad SAS

AF:

0.0419

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.0517

Gnomad NFE

AF:

0.0507

Gnomad OTH

AF:

0.0583

GnomAD2 exomes

AF:

0.0148

AC:

647

AN:

43572

AF XY:

0.0154

show subpopulations

Gnomad AFR exome

AF:

0.00737

Gnomad AMR exome

AF:

0.0283

Gnomad ASJ exome

AF:

0.0252

Gnomad EAS exome

AF:

0.0233

Gnomad FIN exome

AF:

0.0591

Gnomad NFE exome

AF:

0.00784

Gnomad OTH exome

AF:

0.0187

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0138

AC:

6794

AN:

491534

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

3583

AN XY:

246610

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0103

AC:

126

AN:

12220

American (AMR)

AF:

0.0256

AC:

227

AN:

8850

Ashkenazi Jewish (ASJ)

AF:

0.0140

AC:

136

AN:

9716

East Asian (EAS)

AF:

0.00957

AC:

202

AN:

21106

South Asian (SAS)

AF:

0.0457

AC:

768

AN:

16794

European-Finnish (FIN)

AF:

0.0285

AC:

611

AN:

21414

Middle Eastern (MID)

AF:

0.00906

AC:

AN:

1766

European-Non Finnish (NFE)

AF:

0.0118

AC:

4452

AN:

376256

Other (OTH)

AF:

0.0109

AC:

256

AN:

23412

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.286

Heterozygous variant carriers

603

1206

1810

2413

3016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

256

384

512

640

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0401

AC:

1514

AN:

37756

Hom.:

Cov.:

AF XY:

0.0403

AC XY:

746

AN XY:

18494

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0311

AC:

378

AN:

12172

American (AMR)

AF:

0.0372

AC:

145

AN:

3896

Ashkenazi Jewish (ASJ)

AF:

0.0526

AC:

AN:

780

East Asian (EAS)

AF:

0.0170

AC:

AN:

1412

South Asian (SAS)

AF:

0.0422

AC:

AN:

1350

European-Finnish (FIN)

AF:

0.0253

AC:

AN:

2094

Middle Eastern (MID)

AF:

0.0536

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0507

AC:

777

AN:

15324

Other (OTH)

AF:

0.0583

AC:

AN:

480

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

Heterozygous variant carriers

191

382

572

763

954

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:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glaucoma 1, open angle, P

Benign:2

Sep 20, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 25, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Benign:1

Oct 11, 2023

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

-0.74

CADD

Benign

6.0

(source)

DANN

Benign

0.76

PhyloP100

-0.20

PromoterAI

-0.014

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00078

dbscSNV1_RF

Benign

0.012

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