16-2496264-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_001199107.2(TBC1D24):c.116C>T(p.Ala39Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001199107.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBC1D24 | ENST00000646147.1 | c.116C>T | p.Ala39Val | missense_variant | Exon 2 of 8 | NM_001199107.2 | ENSP00000494678.1 | |||
ENSG00000260272 | ENST00000564543.1 | c.116C>T | p.Ala39Val | missense_variant | Exon 1 of 3 | 2 | ENSP00000455547.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152248Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249060Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135268
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461422Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727032
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152366Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74506
ClinVar
Submissions by phenotype
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 Pathogenic:1
PM2_Supporting+PM3_VeryStrong+PP4 -
Autosomal recessive nonsyndromic hearing loss 86 Pathogenic:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive deafness 86 (MIM#614617), DOORS syndrome (MIM#220500), epilepsy, rolandic, with proxysmal exercise-induce dystonia and writer's cramp (MIM#608105), developmental and epileptic encephalopathy 16 (MIM#615338) and familial, infantile myoclonic epilepsy (MIM#605021). Dominant negative or gain of function is suggested mechanism of autosomal dominant deafness, 65 (MIM#616044) (PMID: 27281533). (I) 0106 - This gene is associated with autosomal recessive disease. Autosomal dominant disease is a rare association. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 6 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar and has been observed in many individuals with TBC1D24-related conditions (PMIDs: 28292732, 31112829). (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (c.877C>T; p.(Arg293Cys)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:1
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31618474, 31112829, 28292732, 30180405, 29429257, 30776697) -
Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24 Pathogenic:1
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 39 of the TBC1D24 protein (p.Ala39Val). This variant is present in population databases (rs773916549, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive TBC1D24-related conditions (PMID: 28292732, 30776697, 31112829). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 474302). 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 expected to disrupt TBC1D24 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at