chr6-3224901-G-C
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate
The NM_178012.5(TUBB2B):c.1188C>G(p.His396Gln) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H396R) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 20)
Consequence
TUBB2B
NM_178012.5 missense
NM_178012.5 missense
Scores
9
8
1
Clinical Significance
Conservation
PhyloP100: 5.55
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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-3224902-T-C is described in Lovd as [Pathogenic].
PP2
Missense variant where missense usually causes diseases, TUBB2B
PP3
MetaRNN computational evidence supports a deleterious effect, 0.934
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBB2B | NM_178012.5 | c.1188C>G | p.His396Gln | missense_variant | 4/4 | ENST00000259818.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBB2B | ENST00000259818.8 | c.1188C>G | p.His396Gln | missense_variant | 4/4 | 1 | NM_178012.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 20
GnomAD3 genomes
Cov.:
20
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 20
GnomAD4 genome
Cov.:
20
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 01, 2015 | The H396Q variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H396Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with TUBB2B-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of MoRF binding (P = 0.0882);
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