chr6-3224950-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5PP2PP3_ModeratePP5
The NM_178012.5(TUBB2B):c.1139G>A(p.Arg380His) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R380C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 18)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TUBB2B
NM_178012.5 missense
NM_178012.5 missense
Scores
7
9
2
Clinical Significance
Conservation
PhyloP100: 7.52
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-3224951-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1214258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB2B. . Gene score misZ 5.1195 (greater than the threshold 3.09). Trascript score misZ 6.9522 (greater than threshold 3.09). GenCC has associacion of gene with tubulinopathy-associated dysgyria, congenital fibrosis of extraocular muscles, cerebellar ataxia, intellectual disability, and dysequilibrium, complex cortical dysplasia with other brain malformations 7, complex cortical dysplasia with other brain malformations.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.932
PP5
Variant 6-3224950-C-T is Pathogenic according to our data. Variant chr6-3224950-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2498169.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBB2B | NM_178012.5 | c.1139G>A | p.Arg380His | missense_variant | 4/4 | ENST00000259818.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBB2B | ENST00000259818.8 | c.1139G>A | p.Arg380His | missense_variant | 4/4 | 1 | NM_178012.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 18
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000457 AC: 1AN: 218848Hom.: 0 AF XY: 0.00000830 AC XY: 1AN XY: 120550
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GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1410766Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 699474
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Data not reliable, filtered out with message: AC0;AS_VQSR
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GnomAD4 genome Cov.: 18
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Complex cortical dysplasia with other brain malformations 7 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 22, 2024 | The heterozygous p.Arg380His variant in TUBB2B was identified by our study in one individual with cortical dysplasia, complex, with other brain malformations 7. Trio exome analysis showed this variant to be de novo. The variant has not been previously reported in individuals with cortical dysplasia, complex, with other brain malformations 7 and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 2498169) and has been interpreted as uncertain significance by Invitae and likely pathogenic by Oxford Medical Genetics Laboratories. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in TUBB2B in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Two additional likely pathogenic and pathogenic variants, resulting in a different amino acid change at the same position, (p.Arg380Leu and Arg380Cys), have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (Variation IDs: 160177, 1214258). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant cortical dysplasia, complex, with other brain malformations 7. ACMG/AMP Criteria applied: PS2_Supporting, PM2_Supporting, PP3_Moderate, PP2, PM5 (Richards 2015). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust | Mar 23, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 13, 2023 | This variant disrupts the p.Arg380 amino acid residue in TUBB2B. Other variant(s) that disrupt this residue have been observed in individuals with TUBB2B-related conditions (PMID: 25140959, 31481326), which suggests that this may be a clinically significant amino acid residue. 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. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 380 of the TUBB2B protein (p.Arg380His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cortical brain malformations (Invitae). 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 TUBB2B protein function. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Loss of MoRF binding (P = 0.0193);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at