16-2495933-G-A

Variant names:

• chr16-2495933-G-A
• rs138511243
• NM_001199107.2:c.-115-101G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001199107.2(TBC1D24):​c.-115-101G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 605,334 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (6 hom., cov: 33)
  • Exomes 𝑓: 0.011 (49 hom.)
• Consequence: TBC1D24 NM_001199107.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.220

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-2495933-G-A is Benign according to our data. Variant chr16-2495933-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 675998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00811 (1236/152320) while in subpopulation SAS AF= 0.0164 (79/4822). AF 95% confidence interval is 0.0135. There are 6 homozygotes in gnomad4. There are 641 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D24	NM_001199107.2	c.-115-101G>A		intron_variant	Intron 1 of 7	ENST00000646147.1	NP_001186036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D24	ENST00000646147.1	c.-115-101G>A		intron_variant	Intron 1 of 7		NM_001199107.2	ENSP00000494678.1

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1236 AN: 152202 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.0112 AC: 5070 AN: 453014 Hom.: 49 AF XY: 0.0118 AC XY: 2782 AN XY: 235670

Gnomad4 AFR exome AF: 0.00145

Gnomad4 AMR exome AF: 0.00782

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.0000374

Gnomad4 SAS exome AF: 0.0195

Gnomad4 FIN exome AF: 0.00979

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.00811 AC: 1236 AN: 152320 Hom.: 6 Cov.: 33 AF XY: 0.00861 AC XY: 641 AN XY: 74478

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00692

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00928 Hom.: 0

Bravo AF: 0.00751

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.70

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: rs138511243; hg19: chr16-2545934;