chr12-64455936-T-C

Position:

• chr12-64455936-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013254.4(TBK1):​c.66T>C​(p.Asn22=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 1,613,322 control chromosomes in the GnomAD database, including 1,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (116 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1616 hom.)
• Consequence: TBK1 NM_013254.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.25

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-64455936-T-C is Benign according to our data. Variant chr12-64455936-T-C is described in ClinVar as [Benign]. Clinvar id is 475941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64455936-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.25 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBK1	NM_013254.4	c.66T>C	p.Asn22=	synonymous_variant	2/21	ENST00000331710.10
TBK1	XM_005268809.2	c.66T>C	p.Asn22=	synonymous_variant	2/21
TBK1	XM_005268810.2	c.66T>C	p.Asn22=	synonymous_variant	2/21
TBK1	XR_007063071.1	n.165T>C		non_coding_transcript_exon_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBK1	ENST00000331710.10	c.66T>C	p.Asn22=	synonymous_variant	2/21	1	NM_013254.4	P4

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4551 AN: 152216 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.00827

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0469

Gnomad OTH AF: 0.0205

GnomAD3 exomes AF: 0.0324 AC: 8119 AN: 250762 Hom.: 197 AF XY: 0.0340 AC XY: 4602 AN XY: 135506

Gnomad AFR exome AF: 0.00683

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0315

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0460

Gnomad OTH exome AF: 0.0283

GnomAD4 exome AF: 0.0445 AC: 64951 AN: 1460988 Hom.: 1616 Cov.: 30 AF XY: 0.0447 AC XY: 32480 AN XY: 726770

Gnomad4 AFR exome AF: 0.00613

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.0267

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0338

Gnomad4 FIN exome AF: 0.0379

Gnomad4 NFE exome AF: 0.0506

Gnomad4 OTH exome AF: 0.0337

GnomAD4 genome AF: 0.0299 AC: 4554 AN: 152334 Hom.: 116 Cov.: 32 AF XY: 0.0297 AC XY: 2211 AN XY: 74500

Gnomad4 AFR AF: 0.00825

Gnomad4 AMR AF: 0.0170

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0296

Gnomad4 FIN AF: 0.0412

Gnomad4 NFE AF: 0.0469

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0409 Hom.: 95

Bravo AF: 0.0266

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0434

EpiControl AF: 0.0405

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Glaucoma 1, open angle, P Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Jul 20, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs41292019; hg19: chr12-64849716;