rs184639841

Positions:

• chr16-2500291-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001199107.2(TBC1D24):​c.1326C>T​(p.Tyr442=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,609,178 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (17 hom.)
• Consequence: TBC1D24 NM_001199107.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.78

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 16-2500291-C-T is Benign according to our data. Variant chr16-2500291-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2500291-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00312 (475/152260) while in subpopulation NFE AF= 0.00563 (383/67996). AF 95% confidence interval is 0.00517. There are 0 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D24	NM_001199107.2	c.1326C>T	p.Tyr442=	synonymous_variant	7/8	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1	c.1326C>T	p.Tyr442=	synonymous_variant	7/8		NM_001199107.2	ENSP00000494678	A1

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00267 AC: 623 AN: 233024 Hom.: 3 AF XY: 0.00273 AC XY: 349 AN XY: 127754

Gnomad AFR exome AF: 0.000793

Gnomad AMR exome AF: 0.000796

Gnomad ASJ exome AF: 0.00363

Gnomad EAS exome AF: 0.0000568

Gnomad SAS exome AF: 0.000341

Gnomad FIN exome AF: 0.000346

Gnomad NFE exome AF: 0.00500

Gnomad OTH exome AF: 0.00317

GnomAD4 exome AF: 0.00401 AC: 5845 AN: 1456918 Hom.: 17 Cov.: 33 AF XY: 0.00398 AC XY: 2884 AN XY: 724380

Gnomad4 AFR exome AF: 0.000749

Gnomad4 AMR exome AF: 0.000788

Gnomad4 ASJ exome AF: 0.00281

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000282

Gnomad4 FIN exome AF: 0.000635

Gnomad4 NFE exome AF: 0.00492

Gnomad4 OTH exome AF: 0.00319

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.00302 AC XY: 225 AN XY: 74440

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00563

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00501 Hom.: 1

Bravo AF: 0.00323

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TBC1D24: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2017	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Tyr442Tyr in exon 7 of TBC1D24: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.6% (49/8380) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs184639841). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 28, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 30, 2014	- -

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. -

DOORS syndrome;C0917800:Familial infantile myoclonic epilepsy;C1842531:Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome;C2829265:Autosomal recessive nonsyndromic hearing loss 86;C3809173:Developmental and epileptic encephalopathy, 16;C3892048:Autosomal dominant nonsyndromic hearing loss 65 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 30, 2021

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.2
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs184639841; hg19: chr16-2550292;