Genetic Variant TBKBP1:p.Gln249Glu (chr17-47699430-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394755.1(TBKBP1):c.745C>G(p.Gln249Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,415,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q249K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TBKBP1
NM_001394755.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.82

Publications

0 publications found

Variant links:

Genes affected

TBKBP1 (HGNC:30140): (TBK1 binding protein 1) TBKBP1 is an adaptor protein that binds to TBK1 (MIM 604834) and is part of the interaction network in the TNF (MIM 191160)/NFKB (see MIM 164011) pathway (Bouwmeester et al., 2004 [PubMed 14743216]).[supplied by OMIM, Mar 2008]

TBKBP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08124918).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394755.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBKBP1	NM_001394755.1	MANE Select	c.745C>G	p.Gln249Glu	missense	Exon 6 of 10	NP_001381684.1	A7MCY6-1
TBKBP1	NM_001394756.1		c.745C>G	p.Gln249Glu	missense	Exon 6 of 10	NP_001381685.1	A7MCY6-1
TBKBP1	NM_014726.2		c.745C>G	p.Gln249Glu	missense	Exon 5 of 9	NP_055541.1	A7MCY6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBKBP1	ENST00000578982.6	TSL:3 MANE Select	c.745C>G	p.Gln249Glu	missense	Exon 6 of 10	ENSP00000462339.2	A7MCY6-1
TBKBP1	ENST00000361722.7	TSL:1	c.745C>G	p.Gln249Glu	missense	Exon 5 of 9	ENSP00000354777.3	A7MCY6-1
TBKBP1	ENST00000851181.1		c.745C>G	p.Gln249Glu	missense	Exon 6 of 10	ENSP00000521240.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1415122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701310

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31572

American (AMR)

AF:

0.00

AC:

AN:

36204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23844

East Asian (EAS)

AF:

0.00

AC:

AN:

38962

South Asian (SAS)

AF:

0.00

AC:

AN:

81170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4524

European-Non Finnish (NFE)

AF:

9.16e-7

AC:

AN:

1091844

Other (OTH)

AF:

0.00

AC:

AN:

58150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.010

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.0039

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.77

M_CAP

Benign

0.0071

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.46

PhyloP100

2.8

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.34

REVEL

Benign

0.15

Sift

Benign

0.30

Sift4G

Benign

1.0

Polyphen

0.020

Vest4

0.33

MutPred

0.15

Loss of helix (P = 0.028)

MVP

0.41

MPC

0.42

ClinPred

0.46

GERP RS

5.4

Varity_R

0.13

gMVP

0.059

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over