chr4-106247238-G-GTA

Variant names:

• chr4-106247238-G-GTA
• rs869320769
• NM_001163435.3:c.831_832insTA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001163435.3(TBCK):​c.831_832insTA​(p.Pro278TyrfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBCK NM_001163435.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.182
• Publications: 1 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-106247238-G-GTA is Pathogenic according to our data. Variant chr4-106247238-G-GTA is described in ClinVar as Pathogenic. ClinVar VariationId is 225238.Status of the report is criteria_provided_single_submitter, 1 stars.

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.831_832insTA	p.Pro278TyrfsTer18	frameshift	Exon 10 of 26	NP_001156907.2	Q8TEA7-1
	TBCK	NM_001163436.4		c.831_832insTA	p.Pro278TyrfsTer18	frameshift	Exon 10 of 26	NP_001156908.2	Q8TEA7-1
	TBCK	NM_001163437.3		c.714_715insTA	p.Pro239TyrfsTer18	frameshift	Exon 10 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.831_832insTA	p.Pro278TyrfsTer18	frameshift	Exon 10 of 26	ENSP00000378198.2	Q8TEA7-1
	TBCK	ENST00000394706.7	TSL:1	c.714_715insTA	p.Pro239TyrfsTer18	frameshift	Exon 10 of 26	ENSP00000378196.3	Q8TEA7-2
	TBCK	ENST00000361687.8	TSL:1	c.642_643insTA	p.Pro215TyrfsTer18	frameshift	Exon 8 of 24	ENSP00000355338.4	Q8TEA7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.18
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs869320769; hg19: chr4-107168395; COSMIC: COSV105088194; COSMIC: COSV105088194;