rs869320769

Positions:

• chr4-106247238-G-GTA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001163435.3(TBCK):​c.831_832insTA​(p.Pro278fs) 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

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 225238.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBCK	NM_001163435.3	c.831_832insTA	p.Pro278fs	frameshift_variant	10/26	ENST00000394708.7	NP_001156907.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBCK	ENST00000394708.7	c.831_832insTA	p.Pro278fs	frameshift_variant	10/26	1	NM_001163435.3	ENSP00000378198.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 13, 2016	Variant summary: The c.831_832insTA (p.Pro278Tyrfs) also known as c.642_643insTA (NM_033115.3) variant in TBCK gene is a frameshift change predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population dataset of ExAC. The variant of interest has been reported in 1 affected individual in the literature and was cited as Pathogenic by reputable database/diagnostic center. In addition, in functional studies, cells from homozygous individual demonstrated reduced phosphorylation of the Ser235/ 236 isoform of PS6, suggesting that reduced mTOR signaling is a pathogenic mechanism. Lastly, the variant was identified homozygously in 2 yo male undergoing WES for congenital hypotonia, seizures (intractable and myotonic jerks), macrocephaly, periventricular white matter changes, nystagmus, esotropia and global developmental delays. Taken together, the variant was classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 19, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs869320769; hg19: chr4-107168395;