12-64464320-AT-ATT

Variant names:

• chr12-64464320-A-AT
• rs57810028
• NM_013254.4:c.229-4dupT

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
TBK1	NM_013254.4	c.229-4dupT		splice_region_variant, intron_variant	Intron 3 of 20	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.229-4dupT		splice_region_variant, intron_variant	Intron 3 of 20		XP_005268866.1
TBK1	XM_005268810.2	c.229-4dupT		splice_region_variant, intron_variant	Intron 3 of 20		XP_005268867.1
TBK1	XR_007063071.1	n.328-4dupT		splice_region_variant, intron_variant	Intron 3 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.229-14_229-13insT		intron_variant	Intron 3 of 20	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

GnomAD2 exomes AF: 0.797 AC: 122184 AN: 153360 AF XY: 0.793

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 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

African (AFR) AF: 0.686 AC: 16749 AN: 24408

American (AMR) AF: 0.817 AC: 19520 AN: 23890

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 13787 AN: 17342

East Asian (EAS) AF: 0.766 AC: 22086 AN: 28846

South Asian (SAS) AF: 0.710 AC: 42644 AN: 60098

European-Finnish (FIN) AF: 0.821 AC: 28986 AN: 35298

Middle Eastern (MID) AF: 0.791 AC: 3125 AN: 3952

European-Non Finnish (NFE) AF: 0.795 AC: 652220 AN: 820568

Other (OTH) AF: 0.779 AC: 33586 AN: 43132

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

African (AFR) AF: 0.806 AC: 33116 AN: 41112

American (AMR) AF: 0.936 AC: 14131 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.955 AC: 3300 AN: 3454

East Asian (EAS) AF: 0.919 AC: 4728 AN: 5142

South Asian (SAS) AF: 0.844 AC: 4029 AN: 4772

European-Finnish (FIN) AF: 0.960 AC: 9742 AN: 10146

Middle Eastern (MID) AF: 0.904 AC: 264 AN: 292

European-Non Finnish (NFE) AF: 0.925 AC: 62498 AN: 67596

Other (OTH) AF: 0.907 AC: 1893 AN: 2086

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

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Glaucoma 1, open angle, P Benign:2

Apr 22, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 30, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs57810028; hg19: chr12-64858100;