6-3225361-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_178012.5(TUBB2B):​c.728C>A​(p.Pro243Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 26)

Consequence

TUBB2B
NM_178012.5 missense

Scores

11
5
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.73
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 Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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, 0.957

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TUBB2BNM_178012.5 linkc.728C>A p.Pro243Gln 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.728C>A p.Pro243Gln missense_variant Exon 4 of 4 1 NM_178012.5 ENSP00000259818.6 Q9BVA1

Frequencies

GnomAD3 genomes
Cov.:
26
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
30
DANN
Benign
0.95
DEOGEN2
Uncertain
0.50
T
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Pathogenic
4.3
H
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-7.0
D
REVEL
Pathogenic
0.86
Sift4G
Pathogenic
0.0
D
Polyphen
0.97
D
Vest4
0.78
MutPred
0.86
Loss of methylation at R241 (P = 0.1223);
MVP
0.73
ClinPred
1.0
D
GERP RS
4.2
Varity_R
0.90
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-3225595; API