Genetic Variant NM_144572.2:c.2456A>G (chr15-78003423-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_144572.2(TBC1D2B):c.2456A>G(p.Gln819Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00159 in 1,613,502 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 11 hom. )

Consequence

TBC1D2B
NM_144572.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.10

Publications

6 publications found

Variant links:

Genes affected

TBC1D2B (HGNC:29183): (TBC1 domain family member 2B) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D2B Gene-Disease associations (from GenCC):

neurodevelopmental disorder with seizures and gingival overgrowth
Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

TBC1D2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009497255).

BP6

Variant 15-78003423-T-C is Benign according to our data. Variant chr15-78003423-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 713527.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 = 0.00295 (449/152320) while in subpopulation AFR AF = 0.00486 (202/41566). AF 95% confidence interval is 0.00431. There are 3 homozygotes in GnomAd4. There are 224 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144572.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D2B	NM_144572.2	MANE Select	c.2456A>G	p.Gln819Arg	missense	Exon 11 of 13	NP_653173.1	Q9UPU7-1
TBC1D2B	NM_001387142.1		c.2456A>G	p.Gln819Arg	missense	Exon 11 of 14	NP_001374071.1
TBC1D2B	NM_001387143.1		c.2453A>G	p.Gln818Arg	missense	Exon 11 of 13	NP_001374072.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D2B	ENST00000300584.8	TSL:5 MANE Select	c.2456A>G	p.Gln819Arg	missense	Exon 11 of 13	ENSP00000300584.3	Q9UPU7-1
TBC1D2B	ENST00000409931.7	TSL:1	c.2456A>G	p.Gln819Arg	missense	Exon 11 of 13	ENSP00000387165.3	Q9UPU7-2
TBC1D2B	ENST00000936499.1		c.2459A>G	p.Gln820Arg	missense	Exon 11 of 13	ENSP00000606558.1

Frequencies

GnomAD3 genomes

AF:

0.00296

AC:

450

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00490

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.0158

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00225

AC:

565

AN:

250834

AF XY:

0.00218

show subpopulations

Gnomad AFR exome

AF:

0.00455

Gnomad AMR exome

AF:

0.00296

Gnomad ASJ exome

AF:

0.0138

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00156

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00144

AC:

2109

AN:

1461182

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

1041

AN XY:

726806

show subpopulations

African (AFR)

AF:

0.00338

AC:

113

AN:

33474

American (AMR)

AF:

0.00338

AC:

151

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0168

AC:

440

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000162

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00208

AC:

111

AN:

53346

Middle Eastern (MID)

AF:

0.00798

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000919

AC:

1021

AN:

1111460

Other (OTH)

AF:

0.00353

AC:

213

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

110

220

330

440

550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00295

AC:

449

AN:

152320

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

224

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00486

AC:

202

AN:

41566

American (AMR)

AF:

0.00327

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

68034

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00230

Hom.:

Bravo

AF:

0.00298

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00433

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00182

AC:

221

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.011

Eigen

Benign

0.012

Eigen_PC

Benign

0.021

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.028

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.97

PhyloP100

6.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.2

REVEL

Benign

0.20

Sift

Uncertain

0.015

Sift4G

Benign

0.14

Polyphen

0.64

Vest4

0.59

MVP

0.42

MPC

0.88

ClinPred

0.013

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.32

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over