chr12-64497641-G-T

Position:

• chr12-64497641-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.1960-7G>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001129
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0650

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 12-64497641-G-T is Benign according to our data. Variant chr12-64497641-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 542556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64497641-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.1960-7G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.1960-7G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_005268866.1
TBK1	XM_005268810.2	c.1960-7G>T		splice_region_variant, 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.1960-7G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_013254.4	ENSP00000329967	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 376 AN: 79448 Hom.: 0 Cov.: 23 FAILED QC

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

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

Gnomad4 AFR exome AF: 0.00499

Gnomad4 AMR exome AF: 0.00807

Gnomad4 ASJ exome AF: 0.00674

Gnomad4 EAS exome AF: 0.00690

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.00729

Gnomad4 OTH exome AF: 0.00600

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

Gnomad4 AFR AF: 0.00415

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00422

Gnomad4 EAS AF: 0.00242

Gnomad4 SAS AF: 0.00185

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.00505

Gnomad4 OTH AF: 0.00200

Alfa AF: 0.00569 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.9
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs768189768; hg19: chr12-64891421;