12-64497641-G-A

Variant names:

• chr12-64497641-G-A
• rs768189768
• NM_013254.4:c.1960-7G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_013254.4(TBK1):​c.1960-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBK1 NM_013254.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001559
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).

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.1960-7G>A		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.1960-7G>A		splice_region intron	N/A	ENSP00000329967.5
	TBK1	ENST00000650790.1		c.1960-7G>A		splice_region intron	N/A	ENSP00000498995.1
	TBK1	ENST00000911930.1		c.1960-7G>A		splice_region intron	N/A	ENSP00000581989.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 81786 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000126 AC: 2 AN: 158798 AF XY: 0.0000113

Gnomad AFR exome AF: 0.0000908

Gnomad AMR exome AF: 0.0000691

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: 0.00000549 AC: 4 AN: 729044 Hom.: 0 Cov.: 20 AF XY: 0.00000535 AC XY: 2 AN XY: 373816

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16820

American (AMR) AF: 0.00 AC: 0 AN: 20894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14878

East Asian (EAS) AF: 0.00 AC: 0 AN: 27660

South Asian (SAS) AF: 0.00 AC: 0 AN: 44248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2994

European-Non Finnish (NFE) AF: 0.00000753 AC: 4 AN: 531366

Other (OTH) AF: 0.00 AC: 0 AN: 32132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 81786 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 38730

African (AFR) AF: 0.00 AC: 0 AN: 24388

American (AMR) AF: 0.00 AC: 0 AN: 7370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1950

East Asian (EAS) AF: 0.00 AC: 0 AN: 2978

South Asian (SAS) AF: 0.00 AC: 0 AN: 2772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 37346

Other (OTH) AF: 0.00 AC: 0 AN: 1038

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.7
DANN	Benign	0.61
PhyloP100		0.065
PromoterAI		-0.0093	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.016
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: rs768189768; hg19: chr12-64891421;