rs141806113

Variant names:

• chr12-64484486-A-G
• rs141806113
• NM_013254.4:c.1176A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_013254.4(TBK1):​c.1176A>G​(p.Leu392Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 1,594,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: TBK1 NM_013254.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.718
• Publications: 0 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: Genomics England PanelApp, ClinGen, 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-64484486-A-G is Benign according to our data. Variant chr12-64484486-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 475933.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.718 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	NM_013254.4	MANE Select	c.1176A>G	p.Leu392Leu	synonymous	Exon 9 of 21	NP_037386.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	ENST00000331710.10	TSL:1 MANE Select	c.1176A>G	p.Leu392Leu	synonymous	Exon 9 of 21	ENSP00000329967.5
	TBK1	ENST00000650790.1		c.1176A>G	p.Leu392Leu	synonymous	Exon 9 of 21	ENSP00000498995.1
	TBK1	ENST00000911930.1		c.1176A>G	p.Leu392Leu	synonymous	Exon 9 of 21	ENSP00000581989.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000433 AC: 10 AN: 230978 AF XY: 0.0000559

Gnomad AFR exome AF: 0.000455

Gnomad AMR exome AF: 0.000106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000201 AC: 29 AN: 1441950 Hom.: 0 Cov.: 30 AF XY: 0.0000195 AC XY: 14 AN XY: 716468

African (AFR) AF: 0.000530 AC: 17 AN: 32098

American (AMR) AF: 0.0000766 AC: 3 AN: 39172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 82082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1105714

Other (OTH) AF: 0.000101 AC: 6 AN: 59470

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74356

African (AFR) AF: 0.000627 AC: 26 AN: 41452

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000100 Hom.: 0

Bravo AF: 0.000215

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.5
DANN	Benign	0.35
PhyloP100		0.72

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: rs141806113; hg19: chr12-64878266; COSMIC: COSV100538352;