rs758299397
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_001199107.2(TBC1D24):c.587A>G(p.Lys196Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
TBC1D24
NM_001199107.2 missense
NM_001199107.2 missense
Scores
3
13
Clinical Significance
Conservation
PhyloP100: 4.48
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 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
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.15778527).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBC1D24 | NM_001199107.2 | c.587A>G | p.Lys196Arg | missense_variant | 2/8 | ENST00000646147.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBC1D24 | ENST00000646147.1 | c.587A>G | p.Lys196Arg | missense_variant | 2/8 | NM_001199107.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249142Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135264
GnomAD3 exomes
AF:
AC:
1
AN:
249142
Hom.:
AF XY:
AC XY:
1
AN XY:
135264
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461512Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727066
GnomAD4 exome
AF:
AC:
2
AN:
1461512
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727066
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Bravo
AF:
ExAC
?
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 22, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TBC1D24 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 541319). This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. This variant is present in population databases (rs758299397, gnomAD 0.003%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 196 of the TBC1D24 protein (p.Lys196Arg). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;.;.;L;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;.;.;.;N
Sift
Benign
T;.;T;.;.;.;T
Sift4G
Benign
T;.;T;.;.;T;T
Polyphen
B;B;B;.;.;B;.
Vest4
MutPred
Loss of ubiquitination at K196 (P = 0.0174);Loss of ubiquitination at K196 (P = 0.0174);Loss of ubiquitination at K196 (P = 0.0174);Loss of ubiquitination at K196 (P = 0.0174);Loss of ubiquitination at K196 (P = 0.0174);Loss of ubiquitination at K196 (P = 0.0174);Loss of ubiquitination at K196 (P = 0.0174);
MVP
MPC
0.31, 0.50
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at