6-3224950-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM5PP2PP3_ModeratePP5_Very_Strong

The NM_178012.5(TUBB2B):c.1139G>A(p.Arg380His) variant causes a missense change involving the alteration of a conserved nucleotide. 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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TUBB2B
NM_178012.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

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]

TUBB2B links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

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, 0.932

PP5

Variant 6-3224950-C-T is Pathogenic according to our data. Variant chr6-3224950-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2498169.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
TUBB2B	NM_178012.5 link	c.1139G>A	p.Arg380His	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
TUBB2B	ENST00000259818.8 link	c.1139G>A	p.Arg380His	missense_variant	Exon 4 of 4	1	NM_178012.5	ENSP00000259818.6		Q9BVA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000457

AC:

AN:

218848

Hom.:

AF XY:

0.00000830

AC XY:

AN XY:

120550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1410766

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699474

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 7

Pathogenic:2

Mar 23, 2023

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

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.Arg380His 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 not been previously reported in individuals with cortical dysplasia, complex, with other brain malformations 7 and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 2498169) and has been interpreted as uncertain significance by Invitae and likely pathogenic by Oxford Medical Genetics Laboratories. 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. Two additional likely pathogenic and pathogenic variants, resulting in a different amino acid change at the same position, (p.Arg380Leu and Arg380Cys), have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (Variation IDs: 160177, 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_Supporting, PM2_Supporting, PP3_Moderate, PP2, PM5 (Richards 2015). -

not provided

Pathogenic:1

Aug 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 380 of the TUBB2B protein (p.Arg380His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cortical brain malformation (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 2498169). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TUBB2B protein function with a positive predictive value of 80%. This variant disrupts the p.Arg380 amino acid residue in TUBB2B. Other variant(s) that disrupt this residue have been observed in individuals with TUBB2B-related conditions (PMID: 25140959, 31481326), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.1

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.81

Sift4G

Uncertain

0.048

Polyphen

0.25

Vest4

0.78

MutPred

0.78

Loss of MoRF binding (P = 0.0193);

MVP

0.78

ClinPred

0.99

GERP RS

4.1

Varity_R

0.82

gMVP

0.95

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over