rs587784498

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_178012.5(TUBB2B):​c.1139G>T​(p.Arg380Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R380C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 18)

Consequence

TUBB2B
NM_178012.5 missense

Scores

14
2
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.52
Variant links:
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 Pathogenic. Variant got 17 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-3224951-G-A is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in the TUBB2B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 5.1195 (above the threshold of 3.09). Trascript score misZ: 6.9522 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.986
PP5
Variant 6-3224950-C-A is Pathogenic according to our data. Variant chr6-3224950-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TUBB2BNM_178012.5 linkc.1139G>T p.Arg380Leu missense_variant Exon 4 of 4 ENST00000259818.8 NP_821080.1 Q9BVA1A0A384MEE3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TUBB2BENST00000259818.8 linkc.1139G>T p.Arg380Leu missense_variant Exon 4 of 4 1 NM_178012.5 ENSP00000259818.6 Q9BVA1

Frequencies

GnomAD3 genomes
Cov.:
18
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
18

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 7 Pathogenic:2
Feb 08, 2013
Genetic Services Laboratory, University of Chicago
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 22, 2024
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

The heterozygous p.Arg380Leu 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 also been reported de novo in one individual with polymicrogyria with other brain anomalies (PMID: 23495813) with confirmed paternity and maternity. It was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 160177) and has been interpreted as likely pathogenic by University of Chicago Genetic Services Laboratory. 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. One additional pathogenic variant, resulting in a different amino acid change at the same position (Arg380Cys) has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (Variation ID: 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_Moderate, PM2_Supporting, PP3_Moderate, PP2, PM5 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
D
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.73
T
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Pathogenic
5.0
H
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-3.8
D
REVEL
Pathogenic
0.97
Sift4G
Pathogenic
0.0010
D
Polyphen
0.94
P
Vest4
0.97
MutPred
0.84
Loss of MoRF binding (P = 0.0172);
MVP
0.96
ClinPred
1.0
D
GERP RS
4.1
Varity_R
0.97
gMVP
0.99

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587784498; hg19: chr6-3225184; API