rs863224939
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP2PP3_StrongPP5
The NM_001069.3(TUBB2A):āc.872A>Cā(p.Gln291Pro) 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 10)
Exomes š: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TUBB2A
NM_001069.3 missense
NM_001069.3 missense
Scores
13
3
2
Clinical Significance
Conservation
PhyloP100: 7.78
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 Likely_pathogenic. Variant got 6 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 6-3154329-T-G is Pathogenic according to our data. Variant chr6-3154329-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217024.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBB2A | NM_001069.3 | c.872A>C | p.Gln291Pro | missense_variant | 4/4 | ENST00000333628.4 | |
TUBB2A | NM_001310315.2 | c.617A>C | p.Gln206Pro | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBB2A | ENST00000333628.4 | c.872A>C | p.Gln291Pro | missense_variant | 4/4 | 1 | NM_001069.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 10
GnomAD3 genomes
Cov.:
10
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 950868Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0AN XY: 477354
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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950868
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13
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477354
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GnomAD4 genome Cov.: 10
GnomAD4 genome
Cov.:
10
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Complex cortical dysplasia with other brain malformations 5 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 10, 2022 | ACMG classification criteria: PS4 supporting, PM2 moderate, PM6, PP3 supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Jan 28, 2014 | - - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 02, 2022 | Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28840640, 32203252, 31589614, 25326637) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 23, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TUBB2A protein function. ClinVar contains an entry for this variant (Variation ID: 217024). This missense change has been observed in individual(s) with TUBB2A-related conditions (PMID: 25326637). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 291 of the TUBB2A protein (p.Gln291Pro). - |
TUBB2A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 12, 2023 | The TUBB2A c.872A>C variant is predicted to result in the amino acid substitution p.Gln291Pro. This variant was reported to have occurred de novo in an individual with developmental delay, short stature, seizures, ureteropelvic junction obstruction, constipation, hydronephrosis, clinodactyly, growth hormone deficiency, and Russell Silver syndrome (Lee et al. 2014. PubMed ID: 25326637, eTable 2). This variant was also reported in a presumably unaffected gamete donor in a large carrier screening study (Capalbo A et al 2019. PubMed ID: 31589614, supplemental table S1). At PreventionGenetics, we detected this variant in an individual with a neurodevelopmental phenotype, but it was inherited from a presumably unaffected parent (internal data). This variant has not been reported in a large population database, indicating it is rare. Although we suspect this variant may be pathogenic, at this time the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. - |
Seizure Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
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
P
Vest4
MutPred
Gain of phosphorylation at T290 (P = 0.096);
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