rs35635889

Variant names:

• chr12-64488537-T-C
• rs35635889
• NM_013254.4:c.1391T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013254.4(TBK1):​c.1391T>C​(p.Val464Ala) variant causes a missense change. The variant allele was found at a frequency of 0.019 in 1,604,966 control chromosomes in the GnomAD database, including 317 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.020 (295 hom.)
• Consequence: TBK1 NM_013254.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.58
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044326484).
• BP6: Variant 12-64488537-T-C is Benign according to our data. Variant chr12-64488537-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0141 (2141/152280) while in subpopulation NFE AF = 0.0223 (1519/68030). AF 95% confidence interval is 0.0214. There are 22 homozygotes in GnomAd4. There are 1029 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AD,AR gene

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.1391T>C	p.Val464Ala	missense	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.1391T>C	p.Val464Ala	missense	Exon 12 of 21	ENSP00000329967.5	Q9UHD2
	TBK1	ENST00000650790.1		c.1391T>C	p.Val464Ala	missense	Exon 12 of 21	ENSP00000498995.1	Q9UHD2
	TBK1	ENST00000911930.1		c.1391T>C	p.Val464Ala	missense	Exon 12 of 21	ENSP00000581989.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2140 AN: 152162 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0135 AC: 3268 AN: 242322 AF XY: 0.0136

Gnomad AFR exome AF: 0.00379

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00901

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0195 AC: 28337 AN: 1452686 Hom.: 295 Cov.: 29 AF XY: 0.0189 AC XY: 13627 AN XY: 721956

African (AFR) AF: 0.00362 AC: 120 AN: 33130

American (AMR) AF: 0.00387 AC: 167 AN: 43204

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 273 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.00686 AC: 571 AN: 83284

European-Finnish (FIN) AF: 0.0242 AC: 1286 AN: 53210

Middle Eastern (MID) AF: 0.00419 AC: 24 AN: 5728

European-Non Finnish (NFE) AF: 0.0225 AC: 24920 AN: 1108712

Other (OTH) AF: 0.0162 AC: 976 AN: 60090

GnomAD4 genome AF: 0.0141 AC: 2141 AN: 152280 Hom.: 22 Cov.: 32 AF XY: 0.0138 AC XY: 1029 AN XY: 74452

African (AFR) AF: 0.00322 AC: 134 AN: 41570

American (AMR) AF: 0.00635 AC: 97 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4818

European-Finnish (FIN) AF: 0.0271 AC: 287 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0223 AC: 1519 AN: 68030

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0164 Hom.: 36

Bravo AF: 0.0123

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0241 AC: 93

ESP6500AA AF: 0.00455 AC: 20

ESP6500EA AF: 0.0203 AC: 175

ExAC AF: 0.0132 AC: 1597

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0168

EpiControl AF: 0.0152

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Glaucoma 1, open angle, P (2)
-	-	2	not specified (2)
-	-	1	Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.076	T
Eigen	Benign	0.077
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.63	N
PhyloP100		6.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.11
Sift	Benign	0.33	T
Sift4G	Benign	0.70	T
Polyphen		0.26	B
Vest4		0.17
MPC		0.51
ClinPred		0.016	T
GERP RS		5.3
Varity_R		0.26
gMVP		0.62
Mutation Taster		=79/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35635889; hg19: chr12-64882317;