4-106262103-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001163435.3(TBCK):​c.376C>A​(p.Arg126Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000736 in 1,358,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TBCK NM_001163435.3 synonymous
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP7: Synonymous conserved (PhyloP=2.9 with no splicing effect.

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>A	p.Arg126Arg	synonymous	Exon 4 of 26	NP_001156907.2	Q8TEA7-1
	TBCK	NM_001163436.4		c.376C>A	p.Arg126Arg	synonymous	Exon 4 of 26	NP_001156908.2	Q8TEA7-1
	TBCK	NM_001163437.3		c.376C>A	p.Arg126Arg	synonymous	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>A	p.Arg126Arg	synonymous	Exon 4 of 26	ENSP00000378198.2	Q8TEA7-1
	TBCK	ENST00000394706.7	TSL:1	c.376C>A	p.Arg126Arg	synonymous	Exon 4 of 26	ENSP00000378196.3	Q8TEA7-2
	TBCK	ENST00000361687.8	TSL:1	c.267-10096C>A		intron	N/A	ENSP00000355338.4	Q8TEA7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.36e-7 AC: 1 AN: 1358662 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 670740

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30174

American (AMR) AF: 0.00 AC: 0 AN: 32744

Ashkenazi Jewish (ASJ) AF: 0.0000414 AC: 1 AN: 24128

East Asian (EAS) AF: 0.00 AC: 0 AN: 35082

South Asian (SAS) AF: 0.00 AC: 0 AN: 73716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1052688

Other (OTH) AF: 0.00 AC: 0 AN: 56262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;