17-47696329-G-C

Variant names:

• chr17-47696329-G-C
• NM_001394755.1:c.217G>C

Variant summary

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

The NM_001394755.1(TBKBP1):​c.217G>C​(p.Glu73Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: TBKBP1 NM_001394755.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21

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]

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 rank	MANE	Protein	UniProt
TBKBP1	NM_001394755.1	c.217G>C	p.Glu73Gln	missense_variant	Exon 2 of 10	ENST00000578982.6	NP_001381684.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBKBP1	ENST00000578982.6	c.217G>C	p.Glu73Gln	missense_variant	Exon 2 of 10	3	NM_001394755.1	ENSP00000462339.2
TBKBP1	ENST00000361722.7	c.217G>C	p.Glu73Gln	missense_variant	Exon 1 of 9	1		ENSP00000354777.3
TBKBP1	ENST00000537587.6	c.217G>C	p.Glu73Gln	missense_variant	Exon 2 of 5	3		ENSP00000446365.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460536 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726556

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217G>C (p.E73Q) alteration is located in exon 1 (coding exon 1) of the TBKBP1 gene. This alteration results from a G to C substitution at nucleotide position 217, causing the glutamic acid (E) at amino acid position 73 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.6	.;.;M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	.;D;N;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.78, 0.80
MutPred		0.18		Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);Gain of MoRF binding (P = 0.0316);
MVP		0.56
MPC		1.2
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.59
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-45773695;