12-64464320-AT-ATTT

Position:

• chr12-64464320-AT-ATTT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_013254.4(TBK1):​c.229-5_229-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,147,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 0)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: TBK1 NM_013254.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 12-64464320-A-ATT is Benign according to our data. Variant chr12-64464320-A-ATT is described in ClinVar as [Benign]. Clinvar id is 1981388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000239 (36/150608) while in subpopulation SAS AF= 0.000419 (2/4774). AF 95% confidence interval is 0.000137. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBK1	NM_013254.4	c.229-5_229-4dupTT		splice_region_variant, intron_variant		ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.229-5_229-4dupTT		splice_region_variant, intron_variant			XP_005268866.1
TBK1	XM_005268810.2	c.229-5_229-4dupTT		splice_region_variant, intron_variant			XP_005268867.1
TBK1	XR_007063071.1	n.328-5_328-4dupTT		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.229-5_229-4dupTT		splice_region_variant, intron_variant		1	NM_013254.4	ENSP00000329967.5

Frequencies

GnomAD3 genomes AF: 0.000233 AC: 35 AN: 150498 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.000691

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000222

Gnomad OTH AF: 0.00145

GnomAD4 exome AF: 0.0162 AC: 16166 AN: 997014 Hom.: 0 Cov.: 29 AF XY: 0.0162 AC XY: 8071 AN XY: 497584

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.0225

Gnomad4 ASJ exome AF: 0.0200

Gnomad4 EAS exome AF: 0.0204

Gnomad4 SAS exome AF: 0.0185

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0180

GnomAD4 genome AF: 0.000239 AC: 36 AN: 150608 Hom.: 0 Cov.: 0 AF XY: 0.000218 AC XY: 16 AN XY: 73530

Gnomad4 AFR AF: 0.0000729

Gnomad4 AMR AF: 0.000265

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.000419

Gnomad4 FIN AF: 0.000691

Gnomad4 NFE AF: 0.000222

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.0375 Hom.: 5204

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

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Computational scores

Source: dbNSFP v4.3

Splicing

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;