rs200926225

chr16-2496641-G-Achr16-2496641-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_001199107.2(TBC1D24):c.493G>A(p.Gly165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,612,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G165C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.11

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 -7 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=0.003846109).
• BP6: Variant 16-2496641-G-A is Benign according to our data. Variant chr16-2496641-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207484.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0015 (229/152354) while in subpopulation AFR AF= 0.0044 (183/41578). AF 95% confidence interval is 0.00388. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D24	NM_001199107.2	c.493G>A	p.Gly165Ser	missense_variant	2/8	ENST00000646147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D24	ENST00000646147.1	c.493G>A	p.Gly165Ser	missense_variant	2/8		NM_001199107.2	A1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 223 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000621 AC: 154 AN: 247984 Hom.: 0 AF XY: 0.000527 AC XY: 71 AN XY: 134814

Gnomad AFR exome AF: 0.00545

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00438

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000299 AC: 436 AN: 1460056 Hom.: 0 Cov.: 31 AF XY: 0.000282 AC XY: 205 AN XY: 726412

Gnomad4 AFR exome AF: 0.00454

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.00164 AC XY: 122 AN XY: 74510

Gnomad4 AFR AF: 0.00440

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000446 Hom.: 0

Bravo AF: 0.00148

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00416 AC: 18

ESP6500EA AF: 0.000468 AC: 4

ExAC AF: 0.000660 AC: 80

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 06, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 09, 2016

p.Gly165Ser in exon 2 of TBC1D24: This variant is not expected to have clinical significance because it has been identified in 0.5% (51/9574) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200926225). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 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 condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2021

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2020

This variant is associated with the following publications: (PMID: 24291220) -

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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	11
Dann	Benign	0.73
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.085	N
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.0038	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.28	N;N;N;.;.;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.10	N;.;N;.;.;.;N
Sift	Benign	0.76	T;.;T;.;.;.;T
Sift4G	Benign	0.48	T;.;T;.;.;T;T
Polyphen		0.0010	B;B;B;.;.;B;.
Vest4		0.025
MVP		0.27
MPC		0.34, 0.51
ClinPred		0.00040	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.025
gMVP		0.25

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: rs200926225; hg19: chr16-2546642;