rs200324356

Variant names:

• chr16-2496789-G-A
• rs200324356
• NM_001199107.2:c.641G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2496789-G-A
• chr16-2496789-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001199107.2(TBC1D24):​c.641G>A​(p.Arg214His) variant causes a missense change. The variant allele was found at a frequency of 0.000958 in 1,613,990 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R214C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00079 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (4 hom.)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:6
• Conservation: PhyloP100: 3.99
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• DOORS syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, PanelApp Australia, G2P
• familial infantile myoclonic epilepsy

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
• autosomal dominant nonsyndromic hearing loss 65

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• focal epilepsy-intellectual disability-cerebro-cerebellar malformation

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• progressive myoclonic epilepsy with dystonia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 86

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000260272 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013885826).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000788 (120/152350) while in subpopulation SAS AF = 0.0029 (14/4828). AF 95% confidence interval is 0.00175. There are 1 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D24	NM_001199107.2	c.641G>A	p.Arg214His	missense_variant	Exon 2 of 8	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1	c.641G>A	p.Arg214His	missense_variant	Exon 2 of 8		NM_001199107.2	ENSP00000494678.1
ENSG00000260272	ENST00000564543.1	c.641G>A	p.Arg214His	missense_variant	Exon 1 of 3	2		ENSP00000455547.1

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 121 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000972 AC: 242 AN: 249014 AF XY: 0.00114

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000956

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.000976 AC: 1426 AN: 1461640 Hom.: 4 Cov.: 31 AF XY: 0.00100 AC XY: 730 AN XY: 727140

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00198 AC: 171 AN: 86258

European-Finnish (FIN) AF: 0.0000564 AC: 3 AN: 53180

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.000986 AC: 1096 AN: 1112004

Other (OTH) AF: 0.00118 AC: 71 AN: 60390

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74502

African (AFR) AF: 0.000241 AC: 10 AN: 41578

American (AMR) AF: 0.000588 AC: 9 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000812

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000471 AC: 2

ESP6500EA AF: 0.00141 AC: 12

ExAC AF: 0.00102 AC: 123

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Nov 14, 2018

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified with a second TBC1D24 variant on the opposite allele (in trans) in siblings with nonsyndromic hearing loss in published literature; authors propose that the p.(R214H) variant may be hypomorphic, resulting in a milder phenotype (PMID: 26371875); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27259978, 22277662, 24848745, 29741288, 32987832, 28428906, 34426522, 32860223, 29358611, 28301460, 27281533, 34440452, 35580552, 26371875, 36374051, 33986365, 36515421, 36964972, 37811145, 28951997, 37996878, 24291220, 39336818) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TBC1D24: BP4, BS2 -

not specified Uncertain:2 Benign:1

Sep 24, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg214His variant in TBC1D24 is classified as likely benign due to its high allele frequency. Although it has been reported in trans with a likely pathogenic variant in two Morroccan probands with hearing loss (2/272 alleles), it was also identified at a similar frequency in a race matched control population (1%, 4/400 chromosomes; Bakhchane 2015). Furthermore, this variant has been reported in several populations by gnomAD with a total allele frequency of 0.1% (271/280420) and an allele frequency of 0.19% (58/30602) of South Asian chromosomes including 1 homozygote. ACMG/AMP criteria: BS1. -

Jun 11, 2019

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 86 Pathogenic:1 Uncertain:1

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene (PMID: 27281533). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Only a single missense has been reported to cause autosomal dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (269 heterozygotes, 1 homozygote). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (3 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif, (Rab-GTPase-TBC domain; PDB, NCBI). (N) 0705 - A comparable variant (p.Arg214Cys) has been previous reported as a VUS (ClinVar). (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as a VUS, likely benign and likely pathogenic (ClinVar, LOVD). All reports of this variant being benign are in relation to epilepsy studies (PMID: 24848745, PMID: 29358611), however, this variant has been called a hypomorphic allele, and disease causing within deafness patients (PMID: 26371875, PMID: 28951997). (N) 0901 - Strong evidence for segregation with disease. This variant has been shown to segregate in two families with hearing loss (PMID: 26371875). (P) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease (IGV). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

May 31, 2018

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This recessive variant was identified in two brothers diagnosed with profound bilateral hearing loss. Both patients harbour also a second variant (see below) in this gene in compound heterozygosity -

Developmental and epileptic encephalopathy, 1 Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Mar 22, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R214H variant (also known as c.641G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 641. The arginine at codon 214 is replaced by histidine, an amino acid with highly similar properties. This variant was identified with another TBC1D24 variant in three families with non-syndromic hearing loss; the variant was suggested to act as a hypomorph (Bakhchane A et al. PLoS ONE, 2015 Sep;10:e0138072; Rehman AU et al. Oral Dis, 2017 Jul;23:551-558). This variant was also detected in a patient with neonatal seizures and pervasive developmental disorder; however, the patient also had a de novo KCNQ2 mutation (Della Mina E et al. Eur. J. Hum. Genet., 2015 Mar;23:354-62). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Familial infantile myoclonic epilepsy Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.052	.;T;T;.;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;.;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M;.;.;M;.
PhyloP100		4.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.63	N;.;N;.;.;.;N
REVEL	Benign	0.19
Sift	Benign	0.067	T;.;T;.;.;.;T
Sift4G	Benign	0.23	T;.;T;.;.;T;T
Polyphen		1.0	D;D;D;.;.;D;.
Vest4		0.64
MVP		0.77
MPC		1.1, 1.5
ClinPred		0.046	T
GERP RS		5.4
Varity_R		0.18
gMVP		0.51
Mutation Taster		=81/19	disease causing (ClinVar)

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: rs200324356; hg19: chr16-2546790; COSMIC: COSV53547158; COSMIC: COSV53547158;