rs398122966

Variant names:

• chr16-2496266-C-T
• rs398122966
• NM_001199107.2:c.118C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2496266-C-T
• chr16-2496266-C-G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001199107.2(TBC1D24):​c.118C>T​(p.Arg40Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,461,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001786321: Published in vivo functional studies of transgenic flies demonstrate reduced diffusion of Sky in presynaptic terminals, impaired trafficking of synaptic vesicles, and behavioral deficits, and in vitro functional studies demonstrate reduced binding to phosphatidylinositol 4,5-bisphosphate containing liposomes, and decreased affinity for IP3 (Fischer et al., 2016" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TBC1D24 NM_001199107.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.65
• Publications: 6 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen, Ambry Genetics
• familial infantile myoclonic epilepsy

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• autosomal dominant nonsyndromic hearing loss 65

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 86

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics
• developmental and epileptic encephalopathy, 16

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• 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

ENSG00000260272 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001786321: Published in vivo functional studies of transgenic flies demonstrate reduced diffusion of Sky in presynaptic terminals, impaired trafficking of synaptic vesicles, and behavioral deficits, and in vitro functional studies demonstrate reduced binding to phosphatidylinositol 4,5-bisphosphate containing liposomes, and decreased affinity for IP3 (Fischer et al., 2016; Luthy et al., 2019); SCV002237154: Experimental studies have shown that this missense change affects TBC1D24 function (PMID: 27669036, 31257402).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001199107.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2496267-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 856852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 16-2496266-C-T is Pathogenic according to our data. Variant chr16-2496266-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 91396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199107.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D24	NM_001199107.2	MANE Select	c.118C>T	p.Arg40Cys	missense	Exon 2 of 8	NP_001186036.1	Q9ULP9-1
	TBC1D24	NM_020705.3		c.118C>T	p.Arg40Cys	missense	Exon 2 of 7	NP_065756.1	Q9ULP9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D24	ENST00000646147.1	MANE Select	c.118C>T	p.Arg40Cys	missense	Exon 2 of 8	ENSP00000494678.1	Q9ULP9-1
	TBC1D24	ENST00000567020.7	TSL:1	c.118C>T	p.Arg40Cys	missense	Exon 2 of 7	ENSP00000454408.1	Q9ULP9-2
	ENSG00000260272	ENST00000564543.1	TSL:2	c.118C>T	p.Arg40Cys	missense	Exon 1 of 3	ENSP00000455547.1	H3BQ06

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249082 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461406 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727020

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	DOORS syndrome (3)
1	-	-	Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;na:Caused by mutation in the TBC1 domain family, member 24 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.82		Loss of MoRF binding (P = 0.0059)
MVP		0.90
MPC		1.3
ClinPred		0.98	D
GERP RS		5.6
PromoterAI		-0.0092	Neutral
Varity_R		0.79
gMVP		0.89
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398122966; hg19: chr16-2546267; COSMIC: COSV53546886; COSMIC: COSV53546886;