16-30358207-G-A

Variant names:

• chr16-30358207-G-A
• rs376756550
• NM_015527.4:c.2164C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015527.4(TBC1D10B):​c.2164C>T​(p.Arg722Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,552,890 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R722Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: TBC1D10B NM_015527.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.253

Genes affected

TBC1D10B (HGNC:24510): (TBC1 domain family member 10B) Small G proteins of the RAB family (see MIM 179508) function in intracellular vesicle trafficking by switching from the GTP-bound state to the GDP-bound state with the assistance of guanine nucleotide exchange factors (GEFs; see MIM 609700) and GTPase-activating proteins (GAPs). TBC1D10B functions as a GAP for several proteins of the Rab family (Ishibashi et al., 2009 [PubMed 19077034]).[supplied by OMIM, Nov 2010]

CD2BP2-DT (HGNC:53029): (CD2BP2 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08855179).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D10B	NM_015527.4	c.2164C>T	p.Arg722Trp	missense_variant	Exon 9 of 9	ENST00000409939.8	NP_056342.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D10B	ENST00000409939.8	c.2164C>T	p.Arg722Trp	missense_variant	Exon 9 of 9	1	NM_015527.4	ENSP00000386538.3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000170 AC: 27 AN: 159258 AF XY: 0.000168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000116

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000637

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000190 AC: 266 AN: 1400740 Hom.: 1 Cov.: 31 AF XY: 0.000198 AC XY: 137 AN XY: 690918

African (AFR) AF: 0.0000316 AC: 1 AN: 31644

American (AMR) AF: 0.00 AC: 0 AN: 35794

Ashkenazi Jewish (ASJ) AF: 0.000357 AC: 9 AN: 25190

East Asian (EAS) AF: 0.00 AC: 0 AN: 35824

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79272

European-Finnish (FIN) AF: 0.0000606 AC: 3 AN: 49538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.000226 AC: 244 AN: 1079598

Other (OTH) AF: 0.000138 AC: 8 AN: 58176

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 21 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000579 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.0000650 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2164C>T (p.R722W) alteration is located in exon 9 (coding exon 9) of the TBC1D10B gene. This alteration results from a C to T substitution at nucleotide position 2164, causing the arginine (R) at amino acid position 722 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.25
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.25
MVP		0.068
MPC		0.40
ClinPred		0.12	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.078
gMVP		0.11
Mutation Taster		=97/3	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

Publications

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Other links and lift over

dbSNP: rs376756550; hg19: chr16-30369528;