rs797046074

chr6-3154168-T-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2 PP3_Strong PP5_Very_Strong

The NM_001069.3(TUBB2A):c.1033A>T(p.Ile345Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 10)
• Consequence: TUBB2A NM_001069.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.75

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TUBB2A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 6-3154168-T-A is Pathogenic according to our data. Variant chr6-3154168-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB2A	NM_001069.3	c.1033A>T	p.Ile345Phe	missense_variant	4/4	ENST00000333628.4
TUBB2A	NM_001310315.2	c.778A>T	p.Ile260Phe	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB2A	ENST00000333628.4	c.1033A>T	p.Ile345Phe	missense_variant	4/4	1	NM_001069.3	P1

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 11

GnomAD4 genome Cov.: 10

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 24, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Apr 29, 2014	- -

TUBB2A-related tubulinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 09, 2020

The TUBB2A c.1033A>T (p.Ile345Phe) variant is a missense variant that has been identified in a de novo heterozygous state in an individual with developmental delay, epilepsy, seizures, infantile spasms, perisylvian polymicrogyria, microcephaly and plagiocephaly (Lee et al. 2014). The p.Ile345Phe variant is not found in the Genome Aggregation Database in a region of reasonably good sequence coverage, suggesting that it is a rare variant. Additionally, it is located in a C-terminal domain of the TUBB2A gene that is important for protein interaction (Cai et al. 2020) and in silico tools predict damaging effect of the variant on the protein. Based on the collective evidence and application of the ACMG criteria, the p.Ile345Phe variant is classified as pathogenic for TUBB2A-related tubulinopathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	27
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.75		Loss of ubiquitination at K350 (P = 0.1498);
MVP		0.95
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.76
gMVP		0.95

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

Other links and lift over

dbSNP: rs797046074; hg19: chr6-3154402;