Genetic Variant TBC1D10B:p.Lys726Arg (chr16-30358194-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015527.4(TBC1D10B):c.2177A>G(p.Lys726Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000214 in 1,400,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TBC1D10B
NM_015527.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.308

Variant links:

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]

TBC1D10B links:

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

CD2BP2-DT links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040030032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D10B	NM_015527.4 link	c.2177A>G	p.Lys726Arg	missense_variant	Exon 9 of 9	ENST00000409939.8	NP_056342.3	Q4KMP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D10B	ENST00000409939.8 link	c.2177A>G	p.Lys726Arg	missense_variant	Exon 9 of 9	1	NM_015527.4	ENSP00000386538.3		Q4KMP7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000252

AC:

AN:

158588

Hom.:

AF XY:

0.0000120

AC XY:

AN XY:

83122

show subpopulations

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 SAS exome

AF:

0.0000438

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000162

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.0000214

AC:

AN:

1400304

Hom.:

Cov.:

AF XY:

0.0000232

AC XY:

AN XY:

690644

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000883

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000834

Gnomad4 OTH exome

AF:

0.0000859

GnomAD4 genome

Cov.:

Alfa

AF:

0.000223

Hom.:

ExAC

AF:

0.00000981

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2177A>G (p.K726R) alteration is located in exon 9 (coding exon 9) of the TBC1D10B gene. This alteration results from a A to G substitution at nucleotide position 2177, causing the lysine (K) at amino acid position 726 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0073

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.80

M_CAP

Benign

0.025

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.41

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.71

REVEL

Benign

0.13

Sift

Uncertain

0.0010

Sift4G

Benign

0.62

Polyphen

0.060

Vest4

0.10

MutPred

0.23

Loss of methylation at K726 (P = 0.0032);

MVP

0.19

MPC

0.19

ClinPred

0.048

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.090

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over