chr12-64474308-A-G

Position:

• chr12-64474308-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013254.4(TBK1):​c.619A>G​(p.Ile207Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I207T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBK1 NM_013254.4 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 7.04

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBK1	NM_013254.4	c.619A>G	p.Ile207Val	missense_variant	6/21	ENST00000331710.10
TBK1	XM_005268809.2	c.619A>G	p.Ile207Val	missense_variant	6/21
TBK1	XM_005268810.2	c.619A>G	p.Ile207Val	missense_variant	6/21
TBK1	XR_007063071.1	n.718A>G		non_coding_transcript_exon_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBK1	ENST00000331710.10	c.619A>G	p.Ile207Val	missense_variant	6/21	1	NM_013254.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461828 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.15
Sift	Benign	0.042	D
Sift4G	Uncertain	0.022	D
Polyphen		0.90	P
Vest4		0.32
MutPred		0.62		Loss of stability (P = 0.1171);
MVP		0.32
MPC		0.98
ClinPred		0.87	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.64

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: rs1555203557; hg19: chr12-64868088;