12-64488558-G-C

Variant names:

• chr12-64488558-G-C
• rs369875862
• NM_013254.4:c.1412G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_013254.4(TBK1):​c.1412G>C​(p.Cys471Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000688 in 1,453,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C471Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: TBK1 NM_013254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.27
• Publications: 5 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: Uncertain_significance. The variant received 0 ACMG points.

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.1412G>C	p.Cys471Ser	missense	Exon 12 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.1412G>C	p.Cys471Ser	missense	Exon 12 of 21	ENSP00000329967.5
	TBK1	ENST00000650790.1		c.1412G>C	p.Cys471Ser	missense	Exon 12 of 21	ENSP00000498995.1
	TBK1	ENST00000677641.1		c.1412G>C	p.Cys471Ser	missense	Exon 12 of 21	ENSP00000504637.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1453132 Hom.: 0 Cov.: 29 AF XY: 0.00000692 AC XY: 5 AN XY: 722230

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.00 AC: 0 AN: 43494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.00 AC: 0 AN: 83608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1108594

Other (OTH) AF: 0.00 AC: 0 AN: 60058

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

TBK1-related disorder Uncertain:1

Jan 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TBK1 c.1412G>C variant is predicted to result in the amino acid substitution p.Cys471Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different missense change at the same amino acid position, c.1412G>A (p.Cys471Tyr) has been reported in at least two patients with Amyotrophic Lateral Sclerosis (Cirulli ET et al 2015. PubMed ID: 25700176; de Majo M et al 2018. PubMed ID: 30033073). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

Dec 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 471 of the TBK1 protein (p.Cys471Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TBK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 542551). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TBK1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.070	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.84	L
PhyloP100		5.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.45
Sift	Benign	0.66	T
Sift4G	Benign	0.91	T
Polyphen		0.90	P
Vest4		0.88
MutPred		0.54		Gain of loop (P = 0.0435)
MVP		0.77
MPC		0.83
ClinPred		0.80	D
GERP RS		5.3
Varity_R		0.41
gMVP		0.68
Mutation Taster		=38/62	disease causing

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: rs369875862; hg19: chr12-64882338;