chr12-64488531-CAG-C

Variant names:

• chr12-64488531-CAG-C
• rs1555204731
• NM_013254.4:c.1387_1388delGA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_013254.4(TBK1):​c.1387_1388delGA​(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 NM_013254.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.43
• 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: ClinGen, Genomics England PanelApp, 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: Pathogenic. The variant received 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 VariationId is 542552.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013254.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	NM_013254.4	MANE Select	c.1387_1388delGA	p.Glu463SerfsTer13	frameshift	Exon 12 of 21	NP_037386.1	Q9UHD2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	ENST00000331710.10	TSL:1 MANE Select	c.1387_1388delGA	p.Glu463SerfsTer13	frameshift	Exon 12 of 21	ENSP00000329967.5	Q9UHD2
	TBK1	ENST00000650790.1		c.1387_1388delGA	p.Glu463SerfsTer13	frameshift	Exon 12 of 21	ENSP00000498995.1	Q9UHD2
	TBK1	ENST00000911930.1		c.1387_1388delGA	p.Glu463SerfsTer13	frameshift	Exon 12 of 21	ENSP00000581989.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000415 AC: 1 AN: 240820 AF XY: 0.00

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 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

African (AFR) AF: 0.0000303 AC: 1 AN: 32984

American (AMR) AF: 0.00 AC: 0 AN: 42782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25864

East Asian (EAS) AF: 0.00 AC: 0 AN: 39280

South Asian (SAS) AF: 0.00 AC: 0 AN: 82700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108132

Other (OTH) AF: 0.00 AC: 0 AN: 60016

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (1)
1	-	-	TBK1-related disorder (1)
-	-	-	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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1555204731; hg19: chr12-64882311;