rs41292019

Variant names:

• chr12-64455936-T-C
• rs41292019
• NM_013254.4:c.66T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013254.4(TBK1):​c.66T>C​(p.Asn22Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 1,613,322 control chromosomes in the GnomAD database, including 1,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (116 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1616 hom.)
• Consequence: TBK1 NM_013254.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.25
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-64455936-T-C is Benign according to our data. Variant chr12-64455936-T-C is described in ClinVar as Benign. ClinVar VariationId is 475941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.25 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

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.66T>C	p.Asn22Asn	synonymous	Exon 2 of 21	NP_037386.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	ENST00000331710.10	TSL:1 MANE Select	c.66T>C	p.Asn22Asn	synonymous	Exon 2 of 21	ENSP00000329967.5
	TBK1	ENST00000650790.1		c.66T>C	p.Asn22Asn	synonymous	Exon 2 of 21	ENSP00000498995.1
	TBK1	ENST00000911930.1		c.66T>C	p.Asn22Asn	synonymous	Exon 2 of 21	ENSP00000581989.1

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4551 AN: 152216 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.00827

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0469

Gnomad OTH AF: 0.0205

GnomAD2 exomes AF: 0.0324 AC: 8119 AN: 250762 AF XY: 0.0340

Gnomad AFR exome AF: 0.00683

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0460

Gnomad OTH exome AF: 0.0283

GnomAD4 exome AF: 0.0445 AC: 64951 AN: 1460988 Hom.: 1616 Cov.: 30 AF XY: 0.0447 AC XY: 32480 AN XY: 726770

African (AFR) AF: 0.00613 AC: 205 AN: 33454

American (AMR) AF: 0.0164 AC: 733 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.0267 AC: 696 AN: 26104

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39684

South Asian (SAS) AF: 0.0338 AC: 2910 AN: 86132

European-Finnish (FIN) AF: 0.0379 AC: 2026 AN: 53404

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5762

European-Non Finnish (NFE) AF: 0.0506 AC: 56270 AN: 1111464

Other (OTH) AF: 0.0337 AC: 2035 AN: 60364

GnomAD4 genome AF: 0.0299 AC: 4554 AN: 152334 Hom.: 116 Cov.: 32 AF XY: 0.0297 AC XY: 2211 AN XY: 74500

African (AFR) AF: 0.00825 AC: 343 AN: 41578

American (AMR) AF: 0.0170 AC: 260 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0296 AC: 143 AN: 4830

European-Finnish (FIN) AF: 0.0412 AC: 437 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0469 AC: 3192 AN: 68024

Other (OTH) AF: 0.0203 AC: 43 AN: 2116

Alfa AF: 0.0428 Hom.: 279

Bravo AF: 0.0266

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0434

EpiControl AF: 0.0405

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		2.3
PromoterAI		0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs41292019; hg19: chr12-64849716;