rs201060500

Positions:

• chr16-2496933-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001199107.2(TBC1D24):​c.785C>T​(p.Ser262Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000616 in 1,614,036 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S262S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (2 hom.)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.72

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 -18 ACMG points.

• PM1: In a domain Rab-GAP TBC (size 215) in uniprot entity TBC24_HUMAN there are 39 pathogenic changes around while only 10 benign (80%) in NM_001199107.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070180893).
• BP6: Variant 16-2496933-C-T is Benign according to our data. Variant chr16-2496933-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 195135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2496933-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00194 (295/152356) while in subpopulation AFR AF= 0.00587 (244/41572). AF 95% confidence interval is 0.00526. There are 1 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D24	NM_001199107.2	c.785C>T	p.Ser262Leu	missense_variant	2/8	ENST00000646147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D24	ENST00000646147.1	c.785C>T	p.Ser262Leu	missense_variant	2/8		NM_001199107.2	A1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00586

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000657 AC: 164 AN: 249450 Hom.: 2 AF XY: 0.000554 AC XY: 75 AN XY: 135368

Gnomad AFR exome AF: 0.00588

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000445

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000478 AC: 699 AN: 1461680 Hom.: 2 Cov.: 31 AF XY: 0.000418 AC XY: 304 AN XY: 727162

Gnomad4 AFR exome AF: 0.00588

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000361

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.00174 AC XY: 130 AN XY: 74506

Gnomad4 AFR AF: 0.00587

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000482 Hom.: 0

Bravo AF: 0.00231

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00627 AC: 27

ESP6500EA AF: 0.000587 AC: 5

ExAC AF: 0.000726 AC: 88

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 27, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	This variant is associated with the following publications: (PMID: 24291220) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TBC1D24: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 13, 2017	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ser262Leu in exon 2 of TBC1D24: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (27/4304) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2018

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. -

TBC1D24-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2020

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0070	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;.;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N;.;N;.;.;.;N
Sift	Benign	0.19	T;.;T;.;.;.;T
Sift4G	Benign	0.15	T;.;T;.;.;T;T
Polyphen		0.93	P;P;P;.;.;P;.
Vest4		0.15
MVP		0.52
MPC		0.30, 0.45
ClinPred		0.017	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.50

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: rs201060500; hg19: chr16-2546934; COSMIC: COSV53546113; COSMIC: COSV53546113;