Genetic Variant TBC1D2:p.Arg850Cys (chr9-98200284-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001267571.2(TBC1D2):c.2548C>T(p.Arg850Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00363 in 1,613,882 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 26 hom. )

Consequence

TBC1D2
NM_001267571.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.62

Publications

10 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016935587).

BP6

Variant 9-98200284-G-A is Benign according to our data. Variant chr9-98200284-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 710851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D2	NM_001267571.2 link	c.2548C>T	p.Arg850Cys	missense_variant	Exon 12 of 13	ENST00000465784.7	NP_001254500.1	Q9BYX2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D2	ENST00000465784.7 link	c.2548C>T	p.Arg850Cys	missense_variant	Exon 12 of 13	1	NM_001267571.2	ENSP00000481721.1		Q9BYX2-1

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

453

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00407

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00213

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00409

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00337

AC:

847

AN:

251330

AF XY:

0.00329

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00231

Gnomad NFE exome

AF:

0.00411

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00370

AC:

5403

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

2679

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.00239

AC:

107

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

26132

East Asian (EAS)

AF:

0.000605

AC:

AN:

39700

South Asian (SAS)

AF:

0.00537

AC:

463

AN:

86228

European-Finnish (FIN)

AF:

0.00221

AC:

118

AN:

53412

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00383

AC:

4264

AN:

1111978

Other (OTH)

AF:

0.00401

AC:

242

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

298

596

895

1193

1491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00298

AC:

453

AN:

152090

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.000723

AC:

AN:

41486

American (AMR)

AF:

0.00406

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00213

AC:

AN:

5160

South Asian (SAS)

AF:

0.00394

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00409

AC:

278

AN:

67986

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00379

Hom.:

Bravo

AF:

0.00274

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00329

AC:

399

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00425

EpiControl

AF:

0.00528

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

T;.;.;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.017

T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Pathogenic

3.0

M;.;M;.;.

PhyloP100

5.6

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-6.6

.;D;D;D;D

REVEL

Benign

0.29

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;.;.;D

Vest4

0.65

MVP

0.63

MPC

1.1

ClinPred

0.10

GERP RS

4.5

Varity_R

0.69

gMVP

0.62

Mutation Taster

=85/15

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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chr9-98200284-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over