12-64488477-CTTTT-CTTT

Variant names:

• chr12-64488477-CT-C
• rs201728462
• NM_013254.4:c.1341-3delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_013254.4(TBK1):​c.1341-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,507,074 control chromosomes in the GnomAD database, including 48 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (46 hom.)
• Consequence: TBK1 NM_013254.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.179
• 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 -16 ACMG points.

• BP6: Variant 12-64488477-CT-C is Benign according to our data. Variant chr12-64488477-CT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475934.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 = 0.00602 (916/152120) while in subpopulation NFE AF = 0.00905 (615/67982). AF 95% confidence interval is 0.00845. There are 2 homozygotes in GnomAd4. There are 452 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1341-3delT		splice_region intron	N/A	NP_037386.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	ENST00000331710.10	TSL:1 MANE Select	c.1341-3delT		splice_region intron	N/A	ENSP00000329967.5
	TBK1	ENST00000650790.1		c.1341-3delT		splice_region intron	N/A	ENSP00000498995.1
	TBK1	ENST00000911930.1		c.1341-3delT		splice_region intron	N/A	ENSP00000581989.1

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 917 AN: 152002 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00905

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00697 AC: 1245 AN: 178590 AF XY: 0.00713

Gnomad AFR exome AF: 0.000928

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.00569

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.00906

Gnomad OTH exome AF: 0.00500

GnomAD4 exome AF: 0.00792 AC: 10730 AN: 1354954 Hom.: 46 Cov.: 24 AF XY: 0.00803 AC XY: 5408 AN XY: 673192

African (AFR) AF: 0.000970 AC: 28 AN: 28860

American (AMR) AF: 0.00367 AC: 121 AN: 32944

Ashkenazi Jewish (ASJ) AF: 0.00591 AC: 143 AN: 24202

East Asian (EAS) AF: 0.0000554 AC: 2 AN: 36076

South Asian (SAS) AF: 0.00599 AC: 433 AN: 72340

European-Finnish (FIN) AF: 0.0113 AC: 573 AN: 50516

Middle Eastern (MID) AF: 0.00773 AC: 35 AN: 4530

European-Non Finnish (NFE) AF: 0.00858 AC: 9008 AN: 1049400

Other (OTH) AF: 0.00690 AC: 387 AN: 56086

GnomAD4 genome AF: 0.00602 AC: 916 AN: 152120 Hom.: 2 Cov.: 32 AF XY: 0.00608 AC XY: 452 AN XY: 74382

African (AFR) AF: 0.00157 AC: 65 AN: 41510

American (AMR) AF: 0.00406 AC: 62 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00478 AC: 23 AN: 4816

European-Finnish (FIN) AF: 0.0107 AC: 113 AN: 10566

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.00905 AC: 615 AN: 67982

Other (OTH) AF: 0.00475 AC: 10 AN: 2104

Alfa AF: 0.00702 Hom.: 0

Bravo AF: 0.00503

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism

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: rs201728462; hg19: chr12-64882257;