chr4-106254947-C-A

Variant names:

• chr4-106254947-C-A
• rs12639869
• NM_001163435.3:c.456-2940G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001290768.2(TBCK):​c.-62G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 164,326 control chromosomes in the GnomAD database, including 1,906 homozygotes. 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: 𝑓 0.14 (1703 hom., cov: 32)
  • Exomes 𝑓: 0.18 (203 hom.)
• Consequence: TBCK NM_001290768.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.000007043
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.728
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290768.2. 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.456-2940G>T		intron	N/A	NP_001156907.2	Q8TEA7-1
	TBCK	NM_001290768.2		c.-62G>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 27	NP_001277697.2
	TBCK	NM_001290768.2		c.-62G>T		splice_region	Exon 6 of 27	NP_001277697.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBCK	ENST00000394708.7	TSL:1 MANE Select	c.456-2940G>T		intron	N/A	ENSP00000378198.2	Q8TEA7-1
	TBCK	ENST00000394706.7	TSL:1	c.456-2940G>T		intron	N/A	ENSP00000378196.3	Q8TEA7-2
	TBCK	ENST00000361687.8	TSL:1	c.267-2940G>T		intron	N/A	ENSP00000355338.4	Q8TEA7-3

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21423 AN: 151338 Hom.: 1709 Cov.: 32

Gnomad AFR AF: 0.0699

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.176 AC: 2260 AN: 12872 Hom.: 203 Cov.: 0 AF XY: 0.179 AC XY: 1548 AN XY: 8636

African (AFR) AF: 0.0870 AC: 20 AN: 230

American (AMR) AF: 0.121 AC: 40 AN: 330

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 63 AN: 598

East Asian (EAS) AF: 0.194 AC: 43 AN: 222

South Asian (SAS) AF: 0.229 AC: 463 AN: 2026

European-Finnish (FIN) AF: 0.187 AC: 80 AN: 428

Middle Eastern (MID) AF: 0.137 AC: 219 AN: 1596

European-Non Finnish (NFE) AF: 0.182 AC: 1240 AN: 6806

Other (OTH) AF: 0.145 AC: 92 AN: 636

GnomAD4 genome AF: 0.141 AC: 21418 AN: 151454 Hom.: 1703 Cov.: 32 AF XY: 0.143 AC XY: 10563 AN XY: 74022

African (AFR) AF: 0.0699 AC: 2892 AN: 41358

American (AMR) AF: 0.113 AC: 1721 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3466

East Asian (EAS) AF: 0.138 AC: 714 AN: 5164

South Asian (SAS) AF: 0.251 AC: 1207 AN: 4812

European-Finnish (FIN) AF: 0.199 AC: 2052 AN: 10324

Middle Eastern (MID) AF: 0.100 AC: 29 AN: 290

European-Non Finnish (NFE) AF: 0.175 AC: 11871 AN: 67806

Other (OTH) AF: 0.129 AC: 270 AN: 2098

Alfa AF: 0.151 Hom.: 329

Bravo AF: 0.130

Asia WGS AF: 0.203 AC: 704 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000070
dbscSNV1_RF	Benign	0.0
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: rs12639869; hg19: chr4-107176104;