4-106233044-GC-AT

Variant names:

• chr4-106233044-GC-AT
• NM_001163435.3:c.1532_1533delGCinsAT
• TBCK p.Arg511His

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001163435.3(TBCK):​c.1532_1533delGCinsAT​(p.Arg511His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R511R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBCK NM_001163435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.74
• 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: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• syndromic complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1532_1533delGCinsAT	p.Arg511His	missense	N/A	NP_001156907.2	Q8TEA7-1
	TBCK	NM_001163436.4		c.1532_1533delGCinsAT	p.Arg511His	missense	N/A	NP_001156908.2	Q8TEA7-1
	TBCK	NM_001163437.3		c.1415_1416delGCinsAT	p.Arg472His	missense	N/A	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.1532_1533delGCinsAT	p.Arg511His	missense	N/A	ENSP00000378198.2	Q8TEA7-1
	TBCK	ENST00000394706.7	TSL:1	c.1415_1416delGCinsAT	p.Arg472His	missense	N/A	ENSP00000378196.3	Q8TEA7-2
	TBCK	ENST00000361687.8	TSL:1	c.1343_1344delGCinsAT	p.Arg448His	missense	N/A	ENSP00000355338.4	Q8TEA7-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-107154201;