chr16-2499351-C-T

Variant names:

• chr16-2499351-C-T
• rs73490287
• NM_001199107.2:c.1143-6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001199107.2(TBC1D24):​c.1143-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,612,266 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (100 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (78 hom.)
• Consequence: TBC1D24 NM_001199107.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002650
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.810
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-2499351-C-T is Benign according to our data. Variant chr16-2499351-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

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.1143-6C>T		splice_region intron	N/A	NP_001186036.1	Q9ULP9-1
	TBC1D24	NM_020705.3		c.1125-6C>T		splice_region intron	N/A	NP_065756.1	Q9ULP9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D24	ENST00000646147.1	MANE Select	c.1143-6C>T		splice_region intron	N/A	ENSP00000494678.1	Q9ULP9-1
	TBC1D24	ENST00000567020.7	TSL:1	c.1125-6C>T		splice_region intron	N/A	ENSP00000454408.1	Q9ULP9-2
	ENSG00000260272	ENST00000564543.1	TSL:2	c.965+2238C>T		intron	N/A	ENSP00000455547.1	H3BQ06

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2885 AN: 152144 Hom.: 99 Cov.: 33

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00791

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00465 AC: 1139 AN: 245206 AF XY: 0.00339

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000449

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00208 AC: 3032 AN: 1460004 Hom.: 78 Cov.: 32 AF XY: 0.00175 AC XY: 1269 AN XY: 726170

African (AFR) AF: 0.0664 AC: 2221 AN: 33434

American (AMR) AF: 0.00421 AC: 187 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26064

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39662

South Asian (SAS) AF: 0.000221 AC: 19 AN: 85880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.00763 AC: 44 AN: 5766

European-Non Finnish (NFE) AF: 0.000162 AC: 180 AN: 1111262

Other (OTH) AF: 0.00622 AC: 375 AN: 60330

GnomAD4 genome AF: 0.0190 AC: 2894 AN: 152262 Hom.: 100 Cov.: 33 AF XY: 0.0182 AC XY: 1356 AN XY: 74432

African (AFR) AF: 0.0655 AC: 2720 AN: 41532

American (AMR) AF: 0.00790 AC: 121 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68010

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0102 Hom.: 14

Bravo AF: 0.0214

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Developmental and epileptic encephalopathy, 1;C3892048:Autosomal dominant nonsyndromic hearing loss 65;CN236805:Caused by mutation in the TBC1 domain family, member 24 (1)
-	-	1	DOORS syndrome;C0917800:Familial infantile myoclonic epilepsy;C1842531:Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome;C2829265:Autosomal recessive nonsyndromic hearing loss 86;C3809173:Developmental and epileptic encephalopathy, 16;C3892048:Autosomal dominant nonsyndromic hearing loss 65 (1)
-	-	1	Familial infantile myoclonic epilepsy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.2
DANN	Benign	0.69
PhyloP100		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs73490287; hg19: chr16-2549352;