chr12-64488531-CAG-C

Position:

• chr12-64488531-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000331710.10(TBK1):​c.1387_1388del​(p.Glu463SerfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000276 in 1,450,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TBK1 ENST00000331710.10 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.43

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 12 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
• PP5: Variant 12-64488531-CAG-C is Pathogenic according to our data. Variant chr12-64488531-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 542552.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBK1	NM_013254.4	c.1387_1388del	p.Glu463SerfsTer13	frameshift_variant	12/21	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.1387_1388del	p.Glu463SerfsTer13	frameshift_variant	12/21		XP_005268866.1
TBK1	XM_005268810.2	c.1387_1388del	p.Glu463SerfsTer13	frameshift_variant	12/21		XP_005268867.1
TBK1	XR_007063071.1	n.1486_1487del		non_coding_transcript_exon_variant	12/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.1387_1388del	p.Glu463SerfsTer13	frameshift_variant	12/21	1	NM_013254.4	ENSP00000329967	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000415 AC: 1 AN: 240820 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450644 Hom.: 0 AF XY: 0.00000555 AC XY: 4 AN XY: 720786

Gnomad4 AFR exome AF: 0.0000303

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: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

TBK1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

The TBK1 c.1387_1388delGA variant is predicted to result in a frameshift and premature protein termination (p.Glu463Serfs*13). This variant was reported in an individual with amyotrophic lateral sclerosis (Cirulli et al. 2015. PubMed ID: 25700176, this study's case genotype counts for this variant can be found at http://alsdb.org/). This variant is reported in 0.00091% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in TBK1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 14, 2023

This sequence change creates a premature translational stop signal (p.Glu463Serfs*13) in the TBK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBK1 are known to be pathogenic (PMID: 25803835, 26476236, 26581300). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 25700176). ClinVar contains an entry for this variant (Variation ID: 542552). For these reasons, this variant has been classified as Pathogenic. -

Primary open angle glaucoma;C2750180:Herpes simplex encephalitis, susceptibility to, 1;C4225325:Frontotemporal dementia and/or amyotrophic lateral sclerosis 4;C4693542:Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Pathogenic and reported on 11-09-2017 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

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: rs1555204731; hg19: chr12-64882311;