12-64484420-C-T

Position:

• chr12-64484420-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_013254.4(TBK1):​c.1110C>T​(p.Phe370Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,614,080 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (10 hom.)
• Consequence: TBK1 NM_013254.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00300

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-64484420-C-T is Benign according to our data. Variant chr12-64484420-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64484420-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.003 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00152 (232/152262) while in subpopulation NFE AF= 0.0025 (170/68018). AF 95% confidence interval is 0.00219. There are 0 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 232 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBK1	NM_013254.4	c.1110C>T	p.Phe370Phe	synonymous_variant	9/21	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.1110C>T	p.Phe370Phe	synonymous_variant	9/21		XP_005268866.1
TBK1	XM_005268810.2	c.1110C>T	p.Phe370Phe	synonymous_variant	9/21		XP_005268867.1
TBK1	XR_007063071.1	n.1209C>T		non_coding_transcript_exon_variant	9/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.1110C>T	p.Phe370Phe	synonymous_variant	9/21	1	NM_013254.4	ENSP00000329967.5

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00149 AC: 375 AN: 251294 Hom.: 1 AF XY: 0.00151 AC XY: 205 AN XY: 135826

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00225 AC: 3287 AN: 1461818 Hom.: 10 Cov.: 30 AF XY: 0.00224 AC XY: 1631 AN XY: 727214

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00272

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74460

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00188 Hom.: 0

Bravo AF: 0.00173

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TBK1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.0
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs143590388; hg19: chr12-64878200;