chr4-106262103-G-C

Position:

• chr4-106262103-G-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.376C>G​(p.Arg126Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. R126Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBCK NM_001163435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90

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=0.19993588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBCK	NM_001163435.3	c.376C>G	p.Arg126Gly	missense_variant	4/26	ENST00000394708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBCK	ENST00000394708.7	c.376C>G	p.Arg126Gly	missense_variant	4/26	1	NM_001163435.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.011	T;T;.;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.85	.;D;D;.;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.32	N;N;N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.39	T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;.
Polyphen		0.0	B;B;B;B;.
Vest4		0.30
MutPred		0.50		Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);
MVP		0.59
MPC		0.092
ClinPred		0.58	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.21

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: chr4-107183260;