chr6-3225797-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_178012.5(TUBB2B):​c.292G>A​(p.Gly98Arg) 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)
Failed GnomAD Quality Control

Consequence

TUBB2B
NM_178012.5 missense

Scores

13
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.78
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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, 0.991
PP5
Variant 6-3225797-C-T is Pathogenic according to our data. Variant chr6-3225797-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212497.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TUBB2BNM_178012.5 linkuse as main transcriptc.292G>A p.Gly98Arg missense_variant 4/4 ENST00000259818.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TUBB2BENST00000259818.8 linkuse as main transcriptc.292G>A p.Gly98Arg missense_variant 4/41 NM_178012.5 P1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
151710
Hom.:
0
Cov.:
31
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
151710
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74118
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain: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 submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 29, 2013- -
Likely pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterNov 29, 2021- -
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 17, 2022Advanced 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. ClinVar contains an entry for this variant (Variation ID: 212497). This missense change has been observed in individual(s) with cortical malformations (PMID: 23361065, 24860126). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 98 of the TUBB2B protein (p.Gly98Arg). 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. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 04, 2023The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); 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: 23361065, 24860126, 25059107, 26934450) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.54
D
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Pathogenic
4.6
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-4.6
D
REVEL
Pathogenic
0.84
Sift4G
Uncertain
0.033
D
Polyphen
0.93
P
Vest4
0.99
MutPred
0.92
Loss of ubiquitination at K103 (P = 0.0455);
MVP
0.82
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.83
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: rs797046075; hg19: chr6-3226031; COSMIC: COSV52534455; API