4-106095483-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001163435.3(TBCK):c.2570A>G(p.Glu857Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBCK NM_001163435.3 missense, splice_region
• Scores: Splicing: ADA: 0.07290
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

Genes affected

TBCK (HGNC:28261): (TBC1 domain containing kinase) This gene encodes a protein that contains a protein kinase domain, a Rhodanase-like domain and the Tre-2/Bub2/Cdc16 (TBC) domain. The encoded protein is thought to play a role in actin organization, cell growth and cell proliferation by regulating the mammalian target of the rapamycin (mTOR) signaling pathway. This protein may also be involved in the transcriptional regulation of the components of the mTOR complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14402875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCK	NM_001163435.3	c.2570A>G	p.Glu857Gly	missense_variant, splice_region_variant	25/26	ENST00000394708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCK	ENST00000394708.7	c.2570A>G	p.Glu857Gly	missense_variant, splice_region_variant	25/26	1	NM_001163435.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461146 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726858

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

This variant has not been reported in the literature in individuals affected with TBCK-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 857 of the TBCK protein (p.Glu857Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.026	T;T;.;.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L;L;.;.;L
MutationTaster	Benign	0.52	N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.032
Sift	Benign	0.30	T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B
Vest4		0.25
MutPred		0.52		Gain of catalytic residue at A856 (P = 0.0237);Gain of catalytic residue at A856 (P = 0.0237);.;.;Gain of catalytic residue at A856 (P = 0.0237);
MVP		0.37
MPC		0.084
ClinPred		0.16	T
GERP RS		2.8
Varity_R		0.083
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.073
dbscSNV1_RF	Benign	0.23
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: chr4-107016640;