rs189089167

Variant names:

• chr16-2500474-C-T
• rs189089167
• NM_001199107.2:c.1509C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001199107.2(TBC1D24):​c.1509C>T​(p.Ser503Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,574,478 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (34 hom.)
• Consequence: TBC1D24 NM_001199107.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -4.17
• Publications: 2 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, PanelApp Australia
• 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

ENSG00000260272 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-2500474-C-T is Benign according to our data. Variant chr16-2500474-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1592/152302) while in subpopulation AFR AF = 0.0304 (1264/41562). AF 95% confidence interval is 0.029. There are 25 homozygotes in GnomAd4. There are 753 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR,AD gene

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.1509C>T	p.Ser503Ser	synonymous	Exon 7 of 8	NP_001186036.1	Q9ULP9-1
	TBC1D24	NM_020705.3		c.1491C>T	p.Ser497Ser	synonymous	Exon 6 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.1509C>T	p.Ser503Ser	synonymous	Exon 7 of 8	ENSP00000494678.1	Q9ULP9-1
	TBC1D24	ENST00000567020.7	TSL:1	c.1491C>T	p.Ser497Ser	synonymous	Exon 6 of 7	ENSP00000454408.1	Q9ULP9-2
	ENSG00000260272	ENST00000564543.1	TSL:2	c.965+3361C>T		intron	N/A	ENSP00000455547.1	H3BQ06

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1580 AN: 152184 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00421 AC: 727 AN: 172564 AF XY: 0.00351

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00683

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.000227

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00501

GnomAD4 exome AF: 0.00226 AC: 3214 AN: 1422176 Hom.: 34 Cov.: 33 AF XY: 0.00212 AC XY: 1490 AN XY: 704332

African (AFR) AF: 0.0333 AC: 1083 AN: 32520

American (AMR) AF: 0.00656 AC: 260 AN: 39626

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 286 AN: 25398

East Asian (EAS) AF: 0.000134 AC: 5 AN: 37356

South Asian (SAS) AF: 0.000650 AC: 53 AN: 81566

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48804

Middle Eastern (MID) AF: 0.00772 AC: 42 AN: 5440

European-Non Finnish (NFE) AF: 0.00103 AC: 1126 AN: 1092614

Other (OTH) AF: 0.00608 AC: 358 AN: 58852

GnomAD4 genome AF: 0.0105 AC: 1592 AN: 152302 Hom.: 25 Cov.: 33 AF XY: 0.0101 AC XY: 753 AN XY: 74462

African (AFR) AF: 0.0304 AC: 1264 AN: 41562

American (AMR) AF: 0.0108 AC: 166 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68016

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00557 Hom.: 1

Bravo AF: 0.0121

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	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	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.41
DANN	Benign	0.65
PhyloP100		-4.2
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs189089167; hg19: chr16-2550475;