16-2496317-C-T

Position:

chr16-2496317-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001199107.2(TBC1D24):c.169C>T(p.Arg57Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00207 in 1,613,610 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

TBC1D24
NM_001199107.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:7O:1

Conservation

PhyloP100: 4.00

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 Benign. Variant got -11 ACMG points.

PM1

In a domain Rab-GAP TBC (size 215) in uniprot entity TBC24_HUMAN there are 17 pathogenic changes around while only 3 benign (85%) in NM_001199107.2

BP4

Computational evidence support a benign effect (MetaRNN=0.010109574).

BP6

Variant 16-2496317-C-T is Benign according to our data. Variant chr16-2496317-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195364.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, not_provided=1, Benign=3}. Variant chr16-2496317-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00196 (299/152370) while in subpopulation NFE AF= 0.00282 (192/68030). AF 95% confidence interval is 0.0025. There are 1 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D24	NM_001199107.2 linkuse as main transcript	c.169C>T	p.Arg57Cys	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 linkuse as main transcript	c.169C>T	p.Arg57Cys	missense_variant	2/8		NM_001199107.2	ENSP00000494678.1		Q9ULP9-1
ENSG00000260272	ENST00000564543.1 linkuse as main transcript	c.169C>T	p.Arg57Cys	missense_variant	1/3	2		ENSP00000455547.1		H3BQ06

Frequencies

GnomAD3 genomes

AF:

0.00196

AC:

299

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00894

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00282

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00192

AC:

477

AN:

248928

Hom.:

AF XY:

0.00197

AC XY:

266

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.000389

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00255

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.00208

AC:

3045

AN:

1461240

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

1502

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00953

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00169

Gnomad4 NFE exome

AF:

0.00227

Gnomad4 OTH exome

AF:

0.00190

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152370

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00894

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00282

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00308

Hom.:

Bravo

AF:

0.00197

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000703

AC:

ESP6500EA

AF:

0.00259

AC:

ExAC

AF:

0.00178

AC:

215

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00284

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TBC1D24: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2017	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2023	- -

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 16, 2015	p.Arg57Cys in exon 2 of TBC1D24: This variant is not expected to have clinical s ignificance it has been identified in 0.3% (182/65958) of European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202162520). -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2019

The p.R57C variant (also known as c.169C>T), located in coding exon 1 of the TBC1D24 gene, results from a C to T substitution at nucleotide position 169. The arginine at codon 57 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on data from gnomAD, the T allele has an overall frequency of approximately 0.18% (507/27762) total alleles studied. The highest observed frequency was 1.06% (107/10138) of Ashkenazi Jewish alleles. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Familial infantile myoclonic epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

TBC1D24-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

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

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

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

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.010

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

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.5

L;L;L;.;.;L;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.8

N;.;N;.;.;.;N

REVEL

Benign

0.14

Sift

Uncertain

0.0080

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

Sift4G

Uncertain

0.012

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

Polyphen

0.99

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

Vest4

0.42

MVP

0.75

MPC

1.1, 1.5

ClinPred

0.020

GERP RS

4.6

Varity_R

0.12

gMVP

0.38

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