4-106262103-G-C

Variant names:

• chr4-106262103-G-C
• rs575822089
• NM_001163435.3:c.376C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 17/22 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. 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
• Publications: 0 publications found

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]

TBCK Gene-Disease associations (from GenCC):

• hypotonia, infantile, with psychomotor retardation and characteristic facies 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• syndromic complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

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=0.19993588).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163435.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCK	NM_001163435.3	MANE Select	c.376C>G	p.Arg126Gly	missense	Exon 4 of 26	NP_001156907.2	Q8TEA7-1
	TBCK	NM_001163436.4		c.376C>G	p.Arg126Gly	missense	Exon 4 of 26	NP_001156908.2	Q8TEA7-1
	TBCK	NM_001163437.3		c.376C>G	p.Arg126Gly	missense	Exon 4 of 26	NP_001156909.2	Q8TEA7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCK	ENST00000394708.7	TSL:1 MANE Select	c.376C>G	p.Arg126Gly	missense	Exon 4 of 26	ENSP00000378198.2	Q8TEA7-1
	TBCK	ENST00000394706.7	TSL:1	c.376C>G	p.Arg126Gly	missense	Exon 4 of 26	ENSP00000378196.3	Q8TEA7-2
	TBCK	ENST00000361687.8	TSL:1	c.267-10096C>G		intron	N/A	ENSP00000355338.4	Q8TEA7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.32	N
PhyloP100		2.9
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.13
Sift	Benign	0.39	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.30
MutPred		0.50		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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs575822089; hg19: chr4-107183260;