chr6-3154168-T-A
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2PP3_StrongPP5_Very_Strong
The ENST00000333628.4(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
ENST00000333628.4 missense
ENST00000333628.4 missense
Scores
12
4
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB2A. . Gene score misZ 5.2633 (greater than the threshold 3.09). Trascript score misZ 6.0248 (greater than threshold 3.09). GenCC has associacion of gene with complex cortical dysplasia with other brain malformations 5, tubulinopathy.
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TUBB2A | NM_001069.3 | c.1033A>T | p.Ile345Phe | missense_variant | 4/4 | ENST00000333628.4 | NP_001060.1 | |
TUBB2A | NM_001310315.2 | c.778A>T | p.Ile260Phe | missense_variant | 4/4 | NP_001297244.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TUBB2A | ENST00000333628.4 | c.1033A>T | p.Ile345Phe | missense_variant | 4/4 | 1 | NM_001069.3 | ENSP00000369703 | P1 |
Frequencies
GnomAD3 genomes Cov.: 10
GnomAD3 genomes
Cov.:
10
GnomAD4 exome Cov.: 11
GnomAD4 exome
Cov.:
11
GnomAD4 genome Cov.: 10
GnomAD4 genome
Cov.:
10
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Complex cortical dysplasia with other brain malformations 5 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Apr 29, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 24, 2015 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of ubiquitination at K350 (P = 0.1498);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at