rs35635889

Positions:

chr12-64488537-T-C

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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 links:

TBK1 (HGNC:):

TBK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 475935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64488537-T-C is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBK1	NM_013254.4 linkuse as main transcript	c.1391T>C	p.Val464Ala	missense_variant	12/21	ENST00000331710.10	NP_037386.1	Q9UHD2
TBK1	XM_005268809.2 linkuse as main transcript	c.1391T>C	p.Val464Ala	missense_variant	12/21		XP_005268866.1	Q9UHD2
TBK1	XM_005268810.2 linkuse as main transcript	c.1391T>C	p.Val464Ala	missense_variant	12/21		XP_005268867.1	Q9UHD2
TBK1	XR_007063071.1 linkuse as main transcript	n.1490T>C		non_coding_transcript_exon_variant	12/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10 linkuse as main transcript	c.1391T>C	p.Val464Ala	missense_variant	12/21	1	NM_013254.4	ENSP00000329967.5		Q9UHD2

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

GnomAD3 exomes

AF:

0.0135

AC:

3268

AN:

242322

Hom.:

AF XY:

0.0136

AC XY:

1778

AN XY:

130928

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 SAS exome

AF:

0.00659

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

Gnomad4 AFR exome

AF:

0.00362

Gnomad4 AMR exome

AF:

0.00387

Gnomad4 ASJ exome

AF:

0.0105

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00686

Gnomad4 FIN exome

AF:

0.0242

Gnomad4 NFE exome

AF:

0.0225

Gnomad4 OTH exome

AF:

0.0162

GnomAD4 genome

AF:

0.0141

AC:

2141

AN:

152280

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1029

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00322

Gnomad4 AMR

AF:

0.00635

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00519

Gnomad4 FIN

AF:

0.0271

Gnomad4 NFE

AF:

0.0223

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0181

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TBK1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2020	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Glaucoma 1, open angle, P

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Mar 06, 2016	- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

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

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.31

REVEL

Benign

0.11

Sift

Benign

0.33

Sift4G

Benign

0.70

Polyphen

0.26

Vest4

0.17

MPC

0.51

ClinPred

0.016

GERP RS

5.3

Varity_R

0.26

gMVP

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over