16-2497014-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001199107.2(TBC1D24):c.866C>T(p.Ala289Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

TBC1D24
NM_001199107.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.03

Variant links:

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]

TBC1D24 links:

ENSG00000260272 (HGNC:):

ENSG00000260272 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 16-2497014-C-T is Pathogenic according to our data. Variant chr16-2497014-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 436948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2497014-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D24	NM_001199107.2 link	c.866C>T	p.Ala289Val	missense_variant	Exon 2 of 8	ENST00000646147.1	NP_001186036.1	Q9ULP9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1 link	c.866C>T	p.Ala289Val	missense_variant	Exon 2 of 8		NM_001199107.2	ENSP00000494678.1		Q9ULP9-1
ENSG00000260272	ENST00000564543.1 link	c.866C>T	p.Ala289Val	missense_variant	Exon 1 of 3	2		ENSP00000455547.1		H3BQ06

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461448

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial infantile myoclonic epilepsy

Pathogenic:1

Dec 10, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 16

Pathogenic:1

Feb 08, 2022

Center for Molecular Medicine, Children’s Hospital of Fudan University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24

Pathogenic:1

Feb 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 289 of the TBC1D24 protein (p.Ala289Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive TBD1D24-related conditions (PMID: 31112829). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 436948). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TBC1D24 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.071

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

.;T;T;.;.;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

.;.;D;D;D;D;D

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.62

D;D;D;D;D;D;D

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.8

M;M;M;.;.;M;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.8

D;.;D;.;.;.;D

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

D;.;D;.;.;.;D

Sift4G

Pathogenic

0.0

D;.;D;.;.;D;D

Polyphen

1.0

D;D;D;.;.;D;.

Vest4

0.67

MutPred

0.61

Gain of methylation at K288 (P = 0.0837);Gain of methylation at K288 (P = 0.0837);Gain of methylation at K288 (P = 0.0837);Gain of methylation at K288 (P = 0.0837);Gain of methylation at K288 (P = 0.0837);Gain of methylation at K288 (P = 0.0837);Gain of methylation at K288 (P = 0.0837);

MVP

0.77

MPC

1.0, 1.4

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over