rs199852092

Variant names:

• chr16-2496142-C-T
• rs199852092
• NM_001199107.2:c.-7C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001199107.2(TBC1D24):​c.-7C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,613,640 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: TBC1D24 NM_001199107.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.328

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-2496142-C-T is Benign according to our data. Variant chr16-2496142-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139392.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr16-2496142-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00121 (184/152298) while in subpopulation NFE AF= 0.00219 (149/68020). AF 95% confidence interval is 0.0019. There are 1 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D24	NM_001199107.2	c.-7C>T		5_prime_UTR_variant	Exon 2 of 8	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147	c.-7C>T		5_prime_UTR_variant	Exon 2 of 8		NM_001199107.2	ENSP00000494678.1
ENSG00000260272	ENST00000564543	c.-7C>T		5_prime_UTR_variant	Exon 1 of 3	2		ENSP00000455547.1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152180 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00105 AC: 261 AN: 249090 Hom.: 0 AF XY: 0.00112 AC XY: 151 AN XY: 135308

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.00175 AC: 2559 AN: 1461342 Hom.: 4 Cov.: 31 AF XY: 0.00167 AC XY: 1217 AN XY: 727002

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000453

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152298 Hom.: 1 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74478

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00137

EpiCase AF: 0.00202

EpiControl AF: 0.00255

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 03, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Feb 14, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.-7C>T in exon 1 of TBC1D24: This variant is not expected to have clinical sig nificance because it has been identified in 0.2% (109/65832) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199852092). -

Familial infantile myoclonic epilepsy Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.2
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs199852092; hg19: chr16-2546143; COSMIC: COSV53546401; COSMIC: COSV53546401;