16-2500855-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001199107.2(TBC1D24):​c.1577G>C​(p.Arg526Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TBC1D24
NM_001199107.2 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.83
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBC1D24NM_001199107.2 linkc.1577G>C p.Arg526Pro missense_variant Exon 8 of 8 ENST00000646147.1 NP_001186036.1 Q9ULP9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBC1D24ENST00000646147.1 linkc.1577G>C p.Arg526Pro missense_variant Exon 8 of 8 NM_001199107.2 ENSP00000494678.1 Q9ULP9-1
ENSG00000260272ENST00000564543.1 linkc.965+3742G>C intron_variant Intron 1 of 2 2 ENSP00000455547.1 H3BQ06

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1457374
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
725258
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
May 09, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1577G>C (p.R526P) alteration is located in exon 8 (coding exon 7) of the TBC1D24 gene. This alteration results from a G to C substitution at nucleotide position 1577, causing the arginine (R) at amino acid position 526 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
31
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
.;T;T;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.72
.;.;T;T
M_CAP
Benign
0.030
D
MetaRNN
Pathogenic
0.80
D;D;D;D
MetaSVM
Benign
-0.64
T
MutationAssessor
Pathogenic
3.2
.;M;M;.
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-3.2
D;.;D;.
REVEL
Uncertain
0.30
Sift
Benign
0.056
T;.;T;.
Sift4G
Benign
0.17
T;.;T;T
Polyphen
0.99
D;D;D;D
Vest4
0.65
MutPred
0.68
.;Loss of catalytic residue at R526 (P = 0.0168);Loss of catalytic residue at R526 (P = 0.0168);.;
MVP
0.87
MPC
1.2
ClinPred
0.98
D
GERP RS
3.6
Varity_R
0.96
gMVP
0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2550856; API