rs7486100

Positions:

chr12-64482007-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_013254.4(TBK1):c.978T>A(p.Ile326=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,572,000 control chromosomes in the GnomAD database, including 225,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 16495 hom., cov: 31)

Exomes 𝑓: 0.53 ( 208928 hom. )

Consequence

TBK1
NM_013254.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 12-64482007-T-A is Benign according to our data. Variant chr12-64482007-T-A is described in ClinVar as [Benign]. Clinvar id is 403522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64482007-T-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TBK1	NM_013254.4 linkuse as main transcript	c.978T>A	p.Ile326=	synonymous_variant	8/21	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2 linkuse as main transcript	c.978T>A	p.Ile326=	synonymous_variant	8/21		XP_005268866.1
TBK1	XM_005268810.2 linkuse as main transcript	c.978T>A	p.Ile326=	synonymous_variant	8/21		XP_005268867.1
TBK1	XR_007063071.1 linkuse as main transcript	n.1077T>A		non_coding_transcript_exon_variant	8/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10 linkuse as main transcript	c.978T>A	p.Ile326=	synonymous_variant	8/21	1	NM_013254.4	ENSP00000329967	P4

Frequencies

GnomAD3 genomes

AF:

0.437

AC:

66322

AN:

151878

Hom.:

16494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.200

Gnomad AMI

AF:

0.364

Gnomad AMR

AF:

0.457

Gnomad ASJ

AF:

0.413

Gnomad EAS

AF:

0.331

Gnomad SAS

AF:

0.376

Gnomad FIN

AF:

0.621

Gnomad MID

AF:

0.385

Gnomad NFE

AF:

0.562

Gnomad OTH

AF:

0.424

GnomAD3 exomes

AF:

0.477

AC:

107492

AN:

225502

Hom.:

27199

AF XY:

0.482

AC XY:

59256

AN XY:

123026

show subpopulations

Gnomad AFR exome

AF:

0.201

Gnomad AMR exome

AF:

0.406

Gnomad ASJ exome

AF:

0.414

Gnomad EAS exome

AF:

0.326

Gnomad SAS exome

AF:

0.393

Gnomad FIN exome

AF:

0.610

Gnomad NFE exome

AF:

0.555

Gnomad OTH exome

AF:

0.502

GnomAD4 exome

AF:

0.534

AC:

758964

AN:

1420006

Hom.:

208928

Cov.:

AF XY:

0.531

AC XY:

375105

AN XY:

706796

show subpopulations

Gnomad4 AFR exome

AF:

0.194

Gnomad4 AMR exome

AF:

0.408

Gnomad4 ASJ exome

AF:

0.417

Gnomad4 EAS exome

AF:

0.369

Gnomad4 SAS exome

AF:

0.390

Gnomad4 FIN exome

AF:

0.601

Gnomad4 NFE exome

AF:

0.568

Gnomad4 OTH exome

AF:

0.496

GnomAD4 genome

AF:

0.436

AC:

66332

AN:

151994

Hom.:

16495

Cov.:

AF XY:

0.437

AC XY:

32484

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.200

Gnomad4 AMR

AF:

0.456

Gnomad4 ASJ

AF:

0.413

Gnomad4 EAS

AF:

0.332

Gnomad4 SAS

AF:

0.377

Gnomad4 FIN

AF:

0.621

Gnomad4 NFE

AF:

0.562

Gnomad4 OTH

AF:

0.426

Alfa

AF:

0.509

Hom.:

6632

Bravo

AF:

0.414

Asia WGS

AF:

0.367

AC:

1282

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 73% of patients studied by a panel of primary immunodeficiencies. Number of patients: 69. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2018	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. -

Glaucoma 1, open angle, P

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Apr 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.6

DANN

Benign

0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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