12-64497641-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_013254.4(TBK1):​c.1960-7G>T 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. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0075 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBK1 NM_013254.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001129
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-64497641-G-T is Benign according to our data. Variant chr12-64497641-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 542556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 376 AN: 79448 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00416

Gnomad AMI AF: 0.00649

Gnomad AMR AF: 0.00431

Gnomad ASJ AF: 0.00422

Gnomad EAS AF: 0.00241

Gnomad SAS AF: 0.00184

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00505

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.00503 AC: 798 AN: 158798 AF XY: 0.00474

Gnomad AFR exome AF: 0.00354

Gnomad AMR exome AF: 0.00788

Gnomad ASJ exome AF: 0.00719

Gnomad EAS exome AF: 0.0121

Gnomad FIN exome AF: 0.00643

Gnomad NFE exome AF: 0.00356

Gnomad OTH exome AF: 0.00328

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00751 AC: 5310 AN: 706960 Hom.: 0 Cov.: 20 AF XY: 0.00713 AC XY: 2588 AN XY: 362892

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

African (AFR) AF: 0.00499 AC: 82 AN: 16418

American (AMR) AF: 0.00807 AC: 166 AN: 20572

Ashkenazi Jewish (ASJ) AF: 0.00674 AC: 98 AN: 14540

East Asian (EAS) AF: 0.00690 AC: 188 AN: 27240

South Asian (SAS) AF: 0.0103 AC: 438 AN: 42648

European-Finnish (FIN) AF: 0.0105 AC: 387 AN: 36758

Middle Eastern (MID) AF: 0.00340 AC: 10 AN: 2938

European-Non Finnish (NFE) AF: 0.00729 AC: 3753 AN: 514498

Other (OTH) AF: 0.00600 AC: 188 AN: 31348

⚠️ 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: AS_VQSR AF: 0.00473 AC: 376 AN: 79490 Hom.: 0 Cov.: 23 AF XY: 0.00506 AC XY: 191 AN XY: 37732

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

African (AFR) AF: 0.00415 AC: 99 AN: 23862

American (AMR) AF: 0.00431 AC: 31 AN: 7192

Ashkenazi Jewish (ASJ) AF: 0.00422 AC: 8 AN: 1896

East Asian (EAS) AF: 0.00242 AC: 7 AN: 2894

South Asian (SAS) AF: 0.00185 AC: 5 AN: 2704

European-Finnish (FIN) AF: 0.0119 AC: 39 AN: 3288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 122

European-Non Finnish (NFE) AF: 0.00505 AC: 182 AN: 36070

Other (OTH) AF: 0.00200 AC: 2 AN: 1000

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00569 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.9
DANN	Benign	0.66
PhyloP100		0.065
PromoterAI		-0.0033	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0
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;