16-2496461-T-C

Position:

• chr16-2496461-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001199107.2(TBC1D24):​c.313T>C​(p.Cys105Arg) variant causes a missense 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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.01

Genes affected

TBC1D24 (HGNC:29203): (TBC1 domain family member 24) This gene encodes a protein with a conserved domain, referred to as the TBC domain, characteristic of proteins which interact with GTPases. TBC domain proteins may serve as GTPase-activating proteins for a particular group of GTPases, the Rab (Ras-related proteins in brain) small GTPases which are involved in the regulation of membrane trafficking. Mutations in this gene are associated with familial infantile myoclonic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001199107.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 16-2496461-T-C is Pathogenic according to our data. Variant chr16-2496461-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 183153.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D24	NM_001199107.2	c.313T>C	p.Cys105Arg	missense_variant	2/8	ENST00000646147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D24	ENST00000646147.1	c.313T>C	p.Cys105Arg	missense_variant	2/8		NM_001199107.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

DOORS syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Division of Medical Genetics; Sainte-Justine Hospital

Dec 22, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	.;T;T;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	.;.;T;T;T;T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.3	D;.;D;.;.;.;D
REVEL	Pathogenic	0.86
Sift	Benign	0.066	T;.;D;.;.;.;T
Sift4G	Uncertain	0.0050	D;.;D;.;.;D;D
Polyphen		0.99	D;D;D;.;.;D;.
Vest4		0.97
MutPred		0.84		Loss of catalytic residue at L106 (P = 0.008);Loss of catalytic residue at L106 (P = 0.008);Loss of catalytic residue at L106 (P = 0.008);Loss of catalytic residue at L106 (P = 0.008);Loss of catalytic residue at L106 (P = 0.008);Loss of catalytic residue at L106 (P = 0.008);Loss of catalytic residue at L106 (P = 0.008);
MVP		0.87
MPC		1.5, 1.9
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.73
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044547; hg19: chr16-2546462;