rs747538224

Positions:

chr16-2496993-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_001199107.2(TBC1D24):c.845C>G(p.Pro282Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

TBC1D24
NM_001199107.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:2

Conservation

PhyloP100: 4.05

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 7 ACMG points.

PP5

Variant 16-2496993-C-G is Pathogenic according to our data. Variant chr16-2496993-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.1366477). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D24	NM_001199107.2 link	c.845C>G	p.Pro282Arg	missense_variant	2/8	ENST00000646147.1	NP_001186036.1	Q9ULP9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1 link	c.845C>G	p.Pro282Arg	missense_variant	2/8		NM_001199107.2	ENSP00000494678.1		Q9ULP9-1
ENSG00000260272	ENST00000564543.1 link	c.845C>G	p.Pro282Arg	missense_variant	1/3	2		ENSP00000455547.1		H3BQ06

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000176

AC:

AN:

249376

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135328

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2025	Reported previously in individuals with clinical features consistent with TBC1D24-related DOORS spectrum disorder who also harbored a second TBC1D24 variant (PMID: 27502353, 27281533); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27281533, 31440721, 29100083, 33281559, 27502353, 34926809) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Mar 02, 2020	The p.Pro282Arg variant in the TBC1D24 gene has been previously reported in at least 17 unrelated individuals with seizures and developmental delay, and co-segregated with disease in at least 3 affected relatives from 3 families (Appavu et al., 2016; GeneDx, personal communication, March 2, 2020; Hamdan et al., 2017; Invitae, personal communication, February 12, 2020). All affected individuals were homozygous or compound heterozygous. This variant was determined to be in trans with at least 4 different likely pathogenic or pathogenic variants consistent with autosomal recessive inheritance (GeneDx, personal communication, March 2, 2020; Hamdan et al., 2017; Invitae, personal communication, February 12, 2020). The presence of this variant with a diseaseassociated variant on the opposite allele increases suspicion for its pathogenicity. The p.Pro282Arg variant has also been identified in 45/35,374 Latino chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Pro282Arg variant as pathogenic for autosomal recessive TBC1D24-associated disorders based on the information above. [ACMG evidence codes used: PM2; PM3_verystrong; PP1_moderate; PP3] -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.845C>G (p.P282R) alteration is located in exon 2 (coding exon 1) of the TBC1D24 gene. This alteration results from a C to G substitution at nucleotide position 845, causing the proline (P) at amino acid position 282 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD), the TBC1D24 c.845C>G alteration was observed in 0.02% (46/280780) of total alleles studied, with a frequency of 0.13% (45/35374) in the Latino subpopulation. This variant has been reported in the compound heterozygous state in three individuals with epilepsy (Appavu, 2016; Balestrini, 2016; Hamdan, 2017). The in silico prediction for the p.P282R alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

DOORS syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 22, 2019

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2024

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 282 of the TBC1D24 protein (p.Pro282Arg). This variant is present in population databases (rs747538224, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive epileptic encephalopathy (PMID: 27502353, 29100083; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 207505). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TBC1D24 protein function. For these reasons, this variant has been classified as Pathogenic. -

developmental delay with seizures

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Aug 15, 2016

- -

not specified

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 08, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.081

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.065

MetaRNN

Benign

0.14

T;T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.6

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

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.3

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

REVEL

Uncertain

0.29

Sift

Uncertain

0.018

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

Sift4G

Benign

0.070

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

Polyphen

0.99

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

Vest4

0.88

MutPred

0.46

Gain of MoRF binding (P = 0.0015);Gain of MoRF binding (P = 0.0015);Gain of MoRF binding (P = 0.0015);Gain of MoRF binding (P = 0.0015);Gain of MoRF binding (P = 0.0015);Gain of MoRF binding (P = 0.0015);Gain of MoRF binding (P = 0.0015);

MVP

0.74

MPC

0.99, 1.4

ClinPred

0.27

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

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