chr16-2497051-G-T

Variant names:

• chr16-2497051-G-T
• rs776739391
• NM_001199107.2:c.903G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000564543.1(ENSG00000260272):​c.903G>T​(p.Gln301His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q301Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ENSG00000260272 ENST00000564543.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.389
• Publications: 0 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, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, PanelApp Australia, G2P
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in ENST00000564543.1
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089125395).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000564543.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D24	NM_001199107.2	MANE Select	c.903G>T	p.Gln301His	missense	Exon 2 of 8	NP_001186036.1
	TBC1D24	NM_020705.3		c.903G>T	p.Gln301His	missense	Exon 2 of 7	NP_065756.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D24	ENST00000646147.1	MANE Select	c.903G>T	p.Gln301His	missense	Exon 2 of 8	ENSP00000494678.1
	TBC1D24	ENST00000567020.7	TSL:1	c.903G>T	p.Gln301His	missense	Exon 2 of 7	ENSP00000454408.1
	ENSG00000260272	ENST00000564543.1	TSL:2	c.903G>T	p.Gln301His	missense	Exon 1 of 3	ENSP00000455547.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 247152 AF XY: 0.00000745

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460318 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726514

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L
PhyloP100		0.39
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.068
Sift	Benign	0.67	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.34		Loss of MoRF binding (P = 0.0878)
MVP		0.59
MPC		0.32
ClinPred		0.13	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.036
gMVP		0.29

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: rs776739391; hg19: chr16-2547052;