chr12-64464320-A-AT

Position:

• chr12-64464320-A-AT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_013254.4(TBK1):​c.229-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,208,146 control chromosomes in the GnomAD database, including 369,857 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60292 hom., cov: 0)
  • Exomes 𝑓: 0.79 (309565 hom.)
• Consequence: TBK1 NM_013254.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.04

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 12-64464320-A-AT is Benign according to our data. Variant chr12-64464320-A-AT is described in ClinVar as [Benign]. Clinvar id is 403521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBK1	NM_013254.4	c.229-4dupT		splice_region_variant, intron_variant		ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.229-4dupT		splice_region_variant, intron_variant			XP_005268866.1
TBK1	XM_005268810.2	c.229-4dupT		splice_region_variant, intron_variant			XP_005268867.1
TBK1	XR_007063071.1	n.328-4dupT		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.229-4dupT		splice_region_variant, intron_variant		1	NM_013254.4	ENSP00000329967.5

Frequencies

GnomAD3 genomes AF: 0.893 AC: 134384 AN: 150500 Hom.: 60254 Cov.: 0

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.851

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.955

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.960

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.925

Gnomad OTH AF: 0.907

GnomAD3 exomes AF: 0.797 AC: 122184 AN: 153360 Hom.: 46208 AF XY: 0.793 AC XY: 66132 AN XY: 83392

Gnomad AFR exome AF: 0.718

Gnomad AMR exome AF: 0.828

Gnomad ASJ exome AF: 0.810

Gnomad EAS exome AF: 0.790

Gnomad SAS exome AF: 0.720

Gnomad FIN exome AF: 0.853

Gnomad NFE exome AF: 0.811

Gnomad OTH exome AF: 0.792

GnomAD4 exome AF: 0.787 AC: 832703 AN: 1057534 Hom.: 309565 Cov.: 29 AF XY: 0.785 AC XY: 414192 AN XY: 527788

Gnomad4 AFR exome AF: 0.686

Gnomad4 AMR exome AF: 0.817

Gnomad4 ASJ exome AF: 0.795

Gnomad4 EAS exome AF: 0.766

Gnomad4 SAS exome AF: 0.710

Gnomad4 FIN exome AF: 0.821

Gnomad4 NFE exome AF: 0.795

Gnomad4 OTH exome AF: 0.779

GnomAD4 genome AF: 0.893 AC: 134477 AN: 150612 Hom.: 60292 Cov.: 0 AF XY: 0.894 AC XY: 65721 AN XY: 73536

Gnomad4 AFR AF: 0.806

Gnomad4 AMR AF: 0.936

Gnomad4 ASJ AF: 0.955

Gnomad4 EAS AF: 0.919

Gnomad4 SAS AF: 0.844

Gnomad4 FIN AF: 0.960

Gnomad4 NFE AF: 0.925

Gnomad4 OTH AF: 0.907

Alfa AF: 0.816 Hom.: 5204

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	-	- -
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 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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: Frequency -

Glaucoma 1, open angle, P Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -

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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs57810028; hg19: chr12-64858100;