15-78009007-A-T

Variant names:

• chr15-78009007-A-T
• rs2141643269
• NM_144572.2:c.2378T>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_144572.2(TBC1D2B):​c.2378T>A​(p.Leu793*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBC1D2B NM_144572.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.07
• Publications: 0 publications found

Genes affected

TBC1D2B (HGNC:29183): (TBC1 domain family member 2B) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D2B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with seizures and gingival overgrowth

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 15-78009007-A-T is Pathogenic according to our data. Variant chr15-78009007-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1098844.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144572.2. 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
	TBC1D2B	NM_144572.2	MANE Select	c.2378T>A	p.Leu793*	stop_gained	Exon 10 of 13	NP_653173.1	Q9UPU7-1
	TBC1D2B	NM_001387142.1		c.2378T>A	p.Leu793*	stop_gained	Exon 10 of 14	NP_001374071.1
	TBC1D2B	NM_001387143.1		c.2375T>A	p.Leu792*	stop_gained	Exon 10 of 13	NP_001374072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D2B	ENST00000300584.8	TSL:5 MANE Select	c.2378T>A	p.Leu793*	stop_gained	Exon 10 of 13	ENSP00000300584.3	Q9UPU7-1
	TBC1D2B	ENST00000409931.7	TSL:1	c.2378T>A	p.Leu793*	stop_gained	Exon 10 of 13	ENSP00000387165.3	Q9UPU7-2
	TBC1D2B	ENST00000936499.1		c.2378T>A	p.Leu793*	stop_gained	Exon 10 of 13	ENSP00000606558.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with seizures and gingival overgrowth (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.1
Vest4		0.47
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2141643269; hg19: chr15-78301349;