rs1131690784

Positions:

• chr12-64498014-GCTGAAAATAACCA-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_013254.4(TBK1):​c.2115_2127del​(p.Glu706PhefsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as other (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TBK1 NM_013254.4 frameshift
• Clinical Significance: other criteria provided, single submitter O:1
• Conservation: PhyloP100: 7.76

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0347 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBK1	NM_013254.4	c.2115_2127del	p.Glu706PhefsTer2	frameshift_variant	20/21	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.2115_2127del	p.Glu706PhefsTer2	frameshift_variant	20/21		XP_005268866.1
TBK1	XM_005268810.2	c.2115_2127del	p.Glu706PhefsTer2	frameshift_variant	20/21		XP_005268867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.2115_2127del	p.Glu706PhefsTer2	frameshift_variant	20/21	1	NM_013254.4	ENSP00000329967	P4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: other

Submissions summary: Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Motor neuron disease Other:1

other, criteria provided, single submitter

case-control

Centre for Genomic and Experimental Medicine, University of Edinburgh

Aug 31, 2016

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

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: rs1131690784; hg19: chr12-64891794;