Genetic Variant TBC1D2:p.Arg886Leu (chr9-98199511-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001267571.2(TBC1D2):c.2657G>T(p.Arg886Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R886Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TBC1D2
NM_001267571.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.03

Publications

1 publications found

Variant links:

Genes affected

TBC1D2 (HGNC:18026): (TBC1 domain family member 2) Enables GTPase activator activity and cadherin binding activity. Involved in positive regulation of GTPase activity. Located in several cellular components, including cytoplasmic vesicle; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D2 links:

ENSG00000299446 (HGNC:):

ENSG00000299446 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12954137).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267571.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D2	NM_001267571.2	MANE Select	c.2657G>T	p.Arg886Leu	missense	Exon 13 of 13	NP_001254500.1	Q9BYX2-1
TBC1D2	NM_018421.4		c.2624G>T	p.Arg875Leu	missense	Exon 13 of 13	NP_060891.3	Q9BYX2-2
TBC1D2	NM_001267572.1		c.1277G>T	p.Arg426Leu	missense	Exon 7 of 7	NP_001254501.1	Q9BYX2-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D2	ENST00000465784.7	TSL:1 MANE Select	c.2657G>T	p.Arg886Leu	missense	Exon 13 of 13	ENSP00000481721.1	Q9BYX2-1
TBC1D2	ENST00000375066.6	TSL:1	c.2624G>T	p.Arg875Leu	missense	Exon 13 of 13	ENSP00000364207.5	Q9BYX2-2
TBC1D2	ENST00000375063.5	TSL:1	c.1277G>T	p.Arg426Leu	missense	Exon 7 of 7	ENSP00000364203.1	Q9BYX2-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0044

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.010

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.81

M_CAP

Benign

0.0061

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.89

PhyloP100

3.0

PrimateAI

Benign

0.41

PROVEAN

Benign

0.65

REVEL

Benign

0.051

Sift

Benign

0.64

Sift4G

Benign

0.55

Polyphen

0.0080

Vest4

0.24

MutPred

0.50

Loss of MoRF binding (P = 0.0146)

MVP

0.30

MPC

0.37

ClinPred

0.48

GERP RS

5.4

Varity_R

0.19

gMVP

0.51

Mutation Taster

=80/20

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over