6-3224918-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_178012.5(TUBB2B):​c.1171C>T​(p.Arg391Cys) 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 20)

Consequence

TUBB2B
NM_178012.5 missense

Scores

10
7
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.67
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 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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, 0.95
PP5
Variant 6-3224918-G-A is Pathogenic according to our data. Variant chr6-3224918-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2578313.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TUBB2BNM_178012.5 linkuse as main transcriptc.1171C>T p.Arg391Cys missense_variant 4/4 ENST00000259818.8 NP_821080.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TUBB2BENST00000259818.8 linkuse as main transcriptc.1171C>T p.Arg391Cys missense_variant 4/41 NM_178012.5 ENSP00000259818 P1

Frequencies

GnomAD3 genomes
Cov.:
20
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
20

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 01, 2024Previously reported as a de novo variant in an individual with DandyWalker malformation and anterior commissure agenesis as well as dysmorphic facial features; an inherited variant in another gene associated with this phenotype was also observed (PMID: 34946966); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 27010057, Vita[book]2021, 34946966) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.52
D
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Pathogenic
3.9
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Uncertain
-4.0
D
REVEL
Pathogenic
0.88
Sift4G
Uncertain
0.033
D
Polyphen
0.18
B
Vest4
0.76
MutPred
0.85
Loss of MoRF binding (P = 0.0094);
MVP
0.91
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.75
gMVP
0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-3225152; COSMIC: COSV99455489; API