rs745405784

Positions:

• chr16-2496391-C-G
• chr16-2496391-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001199107.2(TBC1D24):​c.243C>G​(p.Ile81Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.36

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]

ENSG00000260272 (HGNC:):

ACMG classification

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 17 pathogenic changes around while only 3 benign (85%) in NM_001199107.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17697334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D24	NM_001199107.2	c.243C>G	p.Ile81Met	missense_variant	2/8	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1	c.243C>G	p.Ile81Met	missense_variant	2/8		NM_001199107.2	ENSP00000494678.1
ENSG00000260272	ENST00000564543.1	c.243C>G	p.Ile81Met	missense_variant	1/3	2		ENSP00000455547.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0052	.;T;T;.;.;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.78	.;.;T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L;L;L;.;.;L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.81	N;.;N;.;.;.;N
REVEL	Benign	0.20
Sift	Uncertain	0.020	D;.;D;.;.;.;D
Sift4G	Benign	0.087	T;.;T;.;.;T;T
Polyphen		0.98	D;D;D;.;.;D;.
Vest4		0.34
MutPred		0.46		Loss of catalytic residue at I81 (P = 0.0116);Loss of catalytic residue at I81 (P = 0.0116);Loss of catalytic residue at I81 (P = 0.0116);Loss of catalytic residue at I81 (P = 0.0116);Loss of catalytic residue at I81 (P = 0.0116);Loss of catalytic residue at I81 (P = 0.0116);Loss of catalytic residue at I81 (P = 0.0116);
MVP		0.55
MPC		0.56, 0.79
ClinPred		0.60	D
GERP RS		-11
Varity_R		0.12
gMVP		0.56

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: rs745405784; hg19: chr16-2546392;