rs371275822

Positions:

• chr12-64497638-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_013254.4(TBK1):​c.1960-10G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (0 hom., cov: 0)
  • Exomes 𝑓: 0.014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBK1 NM_013254.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0007784
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.199

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-64497638-G-T is Benign according to our data. Variant chr12-64497638-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 475937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64497638-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBK1	NM_013254.4	c.1960-10G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.1960-10G>T		splice_polypyrimidine_tract_variant, intron_variant			XP_005268866.1
TBK1	XM_005268810.2	c.1960-10G>T		splice_polypyrimidine_tract_variant, intron_variant			XP_005268867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.1960-10G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_013254.4	ENSP00000329967	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1514 AN: 37732 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.0526

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.0419

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.0517

Gnomad NFE AF: 0.0507

Gnomad OTH AF: 0.0583

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0138 AC: 6794 AN: 491534 Hom.: 0 Cov.: 17 AF XY: 0.0145 AC XY: 3583 AN XY: 246610

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.0256

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.00957

Gnomad4 SAS exome AF: 0.0457

Gnomad4 FIN exome AF: 0.0285

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0401 AC: 1514 AN: 37756 Hom.: 0 Cov.: 0 AF XY: 0.0403 AC XY: 746 AN XY: 18494

Gnomad4 AFR AF: 0.0311

Gnomad4 AMR AF: 0.0372

Gnomad4 ASJ AF: 0.0526

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.0422

Gnomad4 FIN AF: 0.0253

Gnomad4 NFE AF: 0.0507

Gnomad4 OTH AF: 0.0583

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glaucoma 1, open angle, P Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 25, 2016	- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.0
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00078
dbscSNV1_RF	Benign	0.012
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

Publications

LitVar

Other links and lift over

dbSNP: rs371275822; hg19: chr12-64891418;