Variant chr12-64497641-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_013254.4(TBK1):c.1960-7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 0 hom., cov: 23)

Exomes 𝑓: 0.0075 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TBK1
NM_013254.4 splice_region, intron

Scores

Splicing: ADA: 0.0001129

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0650

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

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

BP6

Variant 12-64497641-G-T is Benign according to our data. Variant chr12-64497641-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 542556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64497641-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TBK1	NM_013254.4 link	c.1960-7G>T	splice_region_variant, intron_variant	Intron 18 of 20	ENST00000331710.10	NP_037386.1	Q9UHD2
TBK1	XM_005268809.2 link	c.1960-7G>T	splice_region_variant, intron_variant	Intron 18 of 20		XP_005268866.1	Q9UHD2
TBK1	XM_005268810.2 link	c.1960-7G>T	splice_region_variant, 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.1960-7G>T		splice_region_variant, intron_variant	Intron 18 of 20	1	NM_013254.4	ENSP00000329967.5		Q9UHD2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

376

AN:

79448

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00416

Gnomad AMI

AF:

0.00649

Gnomad AMR

AF:

0.00431

Gnomad ASJ

AF:

0.00422

Gnomad EAS

AF:

0.00241

Gnomad SAS

AF:

0.00184

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00505

Gnomad OTH

AF:

0.00201

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00751

AC:

5310

AN:

706960

Hom.:

Cov.:

AF XY:

0.00713

AC XY:

2588

AN XY:

362892

show subpopulations

Gnomad4 AFR exome

AF:

0.00499

Gnomad4 AMR exome

AF:

0.00807

Gnomad4 ASJ exome

AF:

0.00674

Gnomad4 EAS exome

AF:

0.00690

Gnomad4 SAS exome

AF:

0.0103

Gnomad4 FIN exome

AF:

0.0105

Gnomad4 NFE exome

AF:

0.00729

Gnomad4 OTH exome

AF:

0.00600

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00473

AC:

376

AN:

79490

Hom.:

Cov.:

AF XY:

0.00506

AC XY:

191

AN XY:

37732

show subpopulations

Gnomad4 AFR

AF:

0.00415

Gnomad4 AMR

AF:

0.00431

Gnomad4 ASJ

AF:

0.00422

Gnomad4 EAS

AF:

0.00242

Gnomad4 SAS

AF:

0.00185

Gnomad4 FIN

AF:

0.0119

Gnomad4 NFE

AF:

0.00505

Gnomad4 OTH

AF:

0.00200

Alfa

AF:

0.00569

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Benign:1

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

May 01, 2018

GeneDx

Significance: Likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.9

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.0

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

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