Genetic Variant TBC1D2:p.Arg894Gln (chr9-98199487-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001267571.2(TBC1D2):c.2681G>A(p.Arg894Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,614,102 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 49 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 45 hom. )

Consequence

TBC1D2
NM_001267571.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.491

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019476414).

BP6

Variant 9-98199487-C-T is Benign according to our data. Variant chr9-98199487-C-T is described in ClinVar as [Benign]. Clinvar id is 771169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1979/152300) while in subpopulation AFR AF= 0.0451 (1876/41564). AF 95% confidence interval is 0.0434. There are 49 homozygotes in gnomad4. There are 909 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D2	NM_001267571.2 link	c.2681G>A	p.Arg894Gln	missense_variant	Exon 13 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.2681G>A	p.Arg894Gln	missense_variant	Exon 13 of 13	1	NM_001267571.2	ENSP00000481721.1		Q9BYX2-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1973

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0451

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00362

AC:

907

AN:

250802

Hom.:

AF XY:

0.00270

AC XY:

366

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.0481

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000318

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00148

AC:

2158

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

951

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0458

Gnomad4 AMR exome

AF:

0.00257

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.000265

Gnomad4 OTH exome

AF:

0.00285

GnomAD4 genome

AF:

0.0130

AC:

1979

AN:

152300

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

909

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0451

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00274

Hom.:

Bravo

AF:

0.0149

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0477

AC:

210

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00454

AC:

551

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0060

T;.;.;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.70

T;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

L;.;.;.

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.95

.;N;N;N

REVEL

Benign

0.039

Sift

Benign

0.36

.;T;T;T

Sift4G

Benign

0.62

T;T;T;T

Polyphen

0.019

B;.;.;B

Vest4

0.052

MVP

0.36

MPC

0.33

ClinPred

0.0032

GERP RS

1.6

Varity_R

0.033

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