rs144370662

chr12-64497257-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_013254.4(TBK1):c.1957G>C(p.Glu653Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000186 in 1,571,566 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: TBK1 NM_013254.4 missense, splice_region
• Scores: Splicing: ADA: 0.001242
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.13

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058166325).
• BP6: Variant 12-64497257-G-C is Benign according to our data. Variant chr12-64497257-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 580527.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000158 (24/152170) while in subpopulation NFE AF= 0.00025 (17/68012). AF 95% confidence interval is 0.000159. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBK1	NM_013254.4	c.1957G>C	p.Glu653Gln	missense_variant, splice_region_variant	18/21	ENST00000331710.10
TBK1	XM_005268809.2	c.1957G>C	p.Glu653Gln	missense_variant, splice_region_variant	18/21
TBK1	XM_005268810.2	c.1957G>C	p.Glu653Gln	missense_variant, splice_region_variant	18/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBK1	ENST00000331710.10	c.1957G>C	p.Glu653Gln	missense_variant, splice_region_variant	18/21	1	NM_013254.4	P4

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000267 AC: 60 AN: 224686 Hom.: 0 AF XY: 0.000279 AC XY: 34 AN XY: 121864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000560

Gnomad ASJ exome AF: 0.000838

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000745

GnomAD4 exome AF: 0.000189 AC: 268 AN: 1419396 Hom.: 1 Cov.: 26 AF XY: 0.000196 AC XY: 138 AN XY: 703240

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.000558

Gnomad4 ASJ exome AF: 0.000729

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.000193

Gnomad4 OTH exome AF: 0.000239

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74332

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.000219

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 653 of the TBK1 protein (p.Glu653Gln). This variant is present in population databases (rs144370662, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (PMID: 28008748). ClinVar contains an entry for this variant (Variation ID: 580527). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

TBK1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	19
Dann	Benign	0.93
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	0.89	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.067
Sift	Benign	0.17	T
Sift4G	Benign	0.34	T
Polyphen		0.0020	B
Vest4		0.18
MVP		0.42
MPC		0.33
ClinPred		0.057	T
GERP RS		5.4
Varity_R		0.29
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.038
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: rs144370662; hg19: chr12-64891037;