rs2808001

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3PM1PP2PP5

The NM_001069.3(TUBB2A):c.743C>T(p.Ala248Val) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005086144: Functional studies have shown missense variants to cause weakened incorporation into cytoskeleton, and potentially impaired heterodimer formation indicating loss of function. However, the mutational spectrum is more suggestive of a dominant negative mechanism (PMID:24702957)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.0036 ( 0 hom., cov: 16)

Exomes 𝑓: 0.000010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TUBB2A
NM_001069.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:2B:1

Conservation

PhyloP100: 9.72

Publications

10 publications found

Variant links:

Genes affected

TUBB2A (HGNC:12412): (tubulin beta 2A class IIa) Microtubules, key participants in processes such as mitosis and intracellular transport, are composed of heterodimers of alpha- and beta-tubulins. The protein encoded by this gene is a beta-tubulin. Defects in this gene are associated with complex cortical dysplasia with other brain malformations-5. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

TUBB2A Gene-Disease associations (from GenCC):

complex cortical dysplasia with other brain malformations 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
tubulinopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

TUBB2A links:

ENSG00000309609 (HGNC:):

ENSG00000309609 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV005086144: Functional studies have shown missense variants to cause weakened incorporation into cytoskeleton, and potentially impaired heterodimer formation indicating loss of function. However, the mutational spectrum is more suggestive of a dominant negative mechanism (PMID: 24702957).; SCV000321988: Published functional studies demonstrate that this variant has a reduced rate of heterodimer incorporation into the in vitro cytoskeleton network in comparison with wild type-expressing cells (Cushion et al., 2014); PMID: 26934450, 24702957, 27770045, 32203252, 32571897; SCV003262008: Experimental studies have shown that this missense change affects TUBB2A function (PMID: 24702957, 29547997).

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001069.3

PP2

Missense variant in the TUBB2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 5.2633 (above the threshold of 3.09). Trascript score misZ: 6.0248 (above the threshold of 3.09). GenCC associations: The gene is linked to complex cortical dysplasia with other brain malformations 5, tubulinopathy.

PP5

Variant 6-3154458-G-A is Pathogenic according to our data. Variant chr6-3154458-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127101.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001069.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2A	NM_001069.3	MANE Select	c.743C>T	p.Ala248Val	missense	Exon 4 of 4	NP_001060.1	Q13885
	TUBB2A	NM_001310315.2		c.488C>T	p.Ala163Val	missense	Exon 4 of 4	NP_001297244.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TUBB2A	ENST00000333628.4	TSL:1 MANE Select	c.743C>T	p.Ala248Val	missense	Exon 4 of 4	ENSP00000369703.2	Q13885
TUBB2A	ENST00000940056.1		c.632C>T	p.Ala211Val	missense	Exon 3 of 3	ENSP00000610115.1
TUBB2A	ENST00000679400.1		n.799C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.00358

AC:

400

AN:

111804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00130

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00654

Gnomad SAS

AF:

0.00133

Gnomad FIN

AF:

0.00121

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000700

Gnomad OTH

AF:

0.00338

GnomAD2 exomes

AF:

0.0000337

AC:

AN:

237044

AF XY:

0.0000308

show subpopulations

Gnomad AFR exome

AF:

0.000142

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.0000477

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000103

AC:

AN:

1457164

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724782

show subpopulations

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

African (AFR)

AF:

0.0000607

AC:

AN:

32928

American (AMR)

AF:

0.00

AC:

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.000104

AC:

AN:

38626

South Asian (SAS)

AF:

0.00

AC:

AN:

86098

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5402

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1110954

Other (OTH)

AF:

0.00

AC:

AN:

60062

⚠️ 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: 0.262

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00360

AC:

403

AN:

111864

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

191

AN XY:

52854

show subpopulations

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

African (AFR)

AF:

0.0141

AC:

346

AN:

24610

American (AMR)

AF:

0.00129

AC:

AN:

11592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3064

East Asian (EAS)

AF:

0.00625

AC:

AN:

3358

South Asian (SAS)

AF:

0.00133

AC:

AN:

3006

European-Finnish (FIN)

AF:

0.00121

AC:

AN:

6616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.0000700

AC:

AN:

57162

Other (OTH)

AF:

0.00336

AC:

AN:

1488

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.254

Heterozygous variant carriers

107

160

214

267

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:

0.00211

Hom.:

ExAC

AF:

0.000174

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Complex cortical dysplasia with other brain malformations 5 (10)

not provided (3)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.1

PhyloP100

9.7

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.86

Sift4G

Uncertain

0.0020

Polyphen

0.0080

Vest4

0.84

MVP

0.76

ClinPred

0.33

GERP RS

5.0

Varity_R

0.74

gMVP

0.96

Mutation Taster

=10/90

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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