NM_001199107.2:c.951C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001199107.2(TBC1D24):​c.951C>T​(p.Thr317Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000935 in 1,604,372 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000098 ( 2 hom. )

Consequence

TBC1D24
NM_001199107.2 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -6.20

Publications

1 publications found
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]
TBC1D24 Gene-Disease associations (from GenCC):
  • DOORS syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, PanelApp Australia, G2P
  • familial infantile myoclonic epilepsy
    Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
  • autosomal dominant nonsyndromic hearing loss 65
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • autosomal dominant nonsyndromic hearing loss
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • malignant migrating partial seizures of infancy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • focal epilepsy-intellectual disability-cerebro-cerebellar malformation
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hearing loss, autosomal recessive
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • progressive myoclonic epilepsy with dystonia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • nonsyndromic genetic hearing loss
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • autosomal recessive nonsyndromic hearing loss 86
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.95).
BP6
Variant 16-2497099-C-T is Benign according to our data. Variant chr16-2497099-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207488.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BP7
Synonymous conserved (PhyloP=-6.2 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000978 (142/1452074) while in subpopulation MID AF = 0.0123 (71/5756). AF 95% confidence interval is 0.01. There are 2 homozygotes in GnomAdExome4. There are 70 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBC1D24NM_001199107.2 linkc.951C>T p.Thr317Thr synonymous_variant Exon 2 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.951C>T p.Thr317Thr synonymous_variant Exon 2 of 8 NM_001199107.2 ENSP00000494678.1 Q9ULP9-1
ENSG00000260272ENST00000564543.1 linkc.951C>T p.Thr317Thr synonymous_variant Exon 1 of 3 2 ENSP00000455547.1 H3BQ06

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152180
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000479
GnomAD2 exomes
AF:
0.0000464
AC:
11
AN:
237108
AF XY:
0.0000617
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000560
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000458
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.0000978
AC:
142
AN:
1452074
Hom.:
2
Cov.:
31
AF XY:
0.0000969
AC XY:
70
AN XY:
722724
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33478
American (AMR)
AF:
0.0000224
AC:
1
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000756
AC:
3
AN:
39696
South Asian (SAS)
AF:
0.0000464
AC:
4
AN:
86236
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
43770
Middle Eastern (MID)
AF:
0.0123
AC:
71
AN:
5756
European-Non Finnish (NFE)
AF:
0.0000459
AC:
51
AN:
1111954
Other (OTH)
AF:
0.000166
AC:
10
AN:
60328
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
8
16
24
32
40
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152298
Hom.:
0
Cov.:
33
AF XY:
0.0000806
AC XY:
6
AN XY:
74472
show subpopulations
African (AFR)
AF:
0.0000481
AC:
2
AN:
41570
American (AMR)
AF:
0.00
AC:
0
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.0136
AC:
4
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68022
Other (OTH)
AF:
0.000474
AC:
1
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000198
Hom.:
0
Bravo
AF:
0.0000642
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:2
Aug 10, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

p.Thr317Thr in exon 2 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 13/265438 total chromosomes in different populations by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766745103). -

Oct 14, 2014
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

not provided Benign:2
May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TBC1D24: BP4, BP7 -

Oct 25, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial infantile myoclonic epilepsy Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Benign:1
Nov 02, 2017
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Jan 28, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.95
CADD
Benign
1.7
DANN
Benign
0.60
PhyloP100
-6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs766745103; hg19: chr16-2547100; COSMIC: COSV99565229; COSMIC: COSV99565229; API