chr6-3225525-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_178012.5(TUBB2B):c.564G>T(p.Ser188Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,570,210 control chromosomes in the GnomAD database, including 1,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S188S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.052 ( 244 hom., cov: 31)

Exomes 𝑓: 0.017 ( 1292 hom. )

Consequence

TUBB2B
NM_178012.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -5.28

Publications

7 publications found

Variant links:

Genes affected

TUBB2B (HGNC:30829): (tubulin beta 2B class IIb) The protein encoded by this gene is a beta isoform of tubulin, which binds GTP and is a major component of microtubules. This gene is highly similar to TUBB2A and TUBB2C. Defects in this gene are a cause of asymmetric polymicrogyria. [provided by RefSeq, Mar 2010]

TUBB2B Gene-Disease associations (from GenCC):

complex cortical dysplasia with other brain malformations
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
complex cortical dysplasia with other brain malformations 7
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
congenital fibrosis of extraocular muscles
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Genomics England PanelApp
tubulinopathy-associated dysgyria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cerebellar ataxia, intellectual disability, and dysequilibrium
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TUBB2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 6-3225525-C-A is Benign according to our data. Variant chr6-3225525-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.28 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB2B	NM_178012.5 link	c.564G>T	p.Ser188Ser	synonymous_variant	Exon 4 of 4	ENST00000259818.8	NP_821080.1	Q9BVA1A0A384MEE3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB2B	ENST00000259818.8 link	c.564G>T	p.Ser188Ser	synonymous_variant	Exon 4 of 4	1	NM_178012.5	ENSP00000259818.6		Q9BVA1

Frequencies

GnomAD3 genomes

AF:

0.0523

AC:

7173

AN:

137108

Hom.:

243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.00434

Gnomad EAS

AF:

0.232

Gnomad SAS

AF:

0.0606

Gnomad FIN

AF:

0.00841

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00187

Gnomad OTH

AF:

0.0416

GnomAD2 exomes

AF:

0.0404

AC:

9283

AN:

230044

AF XY:

0.0346

show subpopulations

Gnomad AFR exome

AF:

0.0911

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.00221

Gnomad EAS exome

AF:

0.205

Gnomad FIN exome

AF:

0.00507

Gnomad NFE exome

AF:

0.000813

Gnomad OTH exome

AF:

0.0218

GnomAD4 exome

AF:

0.0172

AC:

24641

AN:

1433012

Hom.:

1292

Cov.:

AF XY:

0.0172

AC XY:

12263

AN XY:

712252

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0988

AC:

2261

AN:

22890

American (AMR)

AF:

0.173

AC:

7390

AN:

42806

Ashkenazi Jewish (ASJ)

AF:

0.00299

AC:

AN:

26070

East Asian (EAS)

AF:

0.214

AC:

7844

AN:

36632

South Asian (SAS)

AF:

0.0519

AC:

4113

AN:

79268

European-Finnish (FIN)

AF:

0.00763

AC:

394

AN:

51614

Middle Eastern (MID)

AF:

0.0154

AC:

AN:

5530

European-Non Finnish (NFE)

AF:

0.000982

AC:

1090

AN:

1109902

Other (OTH)

AF:

0.0238

AC:

1386

AN:

58300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.391

Heterozygous variant carriers

1036

2071

3107

4142

5178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.0524

AC:

7190

AN:

137198

Hom.:

244

Cov.:

AF XY:

0.0569

AC XY:

3813

AN XY:

66976

show subpopulations

African (AFR)

AF:

0.131

AC:

3773

AN:

28844

American (AMR)

AF:

0.120

AC:

1745

AN:

14600

Ashkenazi Jewish (ASJ)

AF:

0.00434

AC:

AN:

3456

East Asian (EAS)

AF:

0.233

AC:

1091

AN:

4680

South Asian (SAS)

AF:

0.0598

AC:

269

AN:

4498

European-Finnish (FIN)

AF:

0.00841

AC:

AN:

10220

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00187

AC:

127

AN:

67756

Other (OTH)

AF:

0.0418

AC:

AN:

1940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

240

480

719

959

1199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.00706

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 19, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 30, 2025

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

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.20

(source)

DANN

Benign

0.65

PhyloP100

-5.3

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over