12-64488572-GAAA-GAA

Variant names:

• chr12-64488572-GA-G
• rs1131690783
• NM_013254.4:c.1432delA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_013254.4(TBK1):​c.1432delA​(p.Thr478LeufsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as other (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBK1 NM_013254.4 frameshift
• Clinical Significance: other criteria provided, single submitter O:1
• Conservation: PhyloP100: 7.65

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBK1	NM_013254.4	c.1432delA	p.Thr478LeufsTer2	frameshift_variant	Exon 12 of 21	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.1432delA	p.Thr478LeufsTer2	frameshift_variant	Exon 12 of 21		XP_005268866.1
TBK1	XM_005268810.2	c.1432delA	p.Thr478LeufsTer2	frameshift_variant	Exon 12 of 21		XP_005268867.1
TBK1	XR_007063071.1	n.1531delA		non_coding_transcript_exon_variant	Exon 12 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.1432delA	p.Thr478LeufsTer2	frameshift_variant	Exon 12 of 21	1	NM_013254.4	ENSP00000329967.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448646 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 719926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: other

Submissions summary: Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Motor neuron disease Other:1

Aug 31, 2016

Centre for Genomic and Experimental Medicine, University of Edinburgh

Significance: other

Review Status: criteria provided, single submitter

Collection Method: case-control

Loss-of-function but lacking segregation data Loss-of-function

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: rs1131690783; hg19: chr12-64882352;