6-3224950-C-A

Position:

• chr6-3224950-C-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_178012.5(TUBB2B):​c.1139G>T​(p.Arg380Leu) 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 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)
• Consequence: TUBB2B NM_178012.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-3224951-G-A is described in Lovd as [Likely_pathogenic].
• 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, 0.986
• PP5: Variant 6-3224950-C-A is Pathogenic according to our data. Variant chr6-3224950-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB2B	NM_178012.5	c.1139G>T	p.Arg380Leu	missense_variant	4/4	ENST00000259818.8	NP_821080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB2B	ENST00000259818.8	c.1139G>T	p.Arg380Leu	missense_variant	4/4	1	NM_178012.5	ENSP00000259818	P1

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 18

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 7 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 22, 2024	The heterozygous p.Arg380Leu 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 also been reported de novo in one individual with polymicrogyria with other brain anomalies (PMID: 23495813) with confirmed paternity and maternity. It was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 160177) and has been interpreted as likely pathogenic by University of Chicago Genetic Services Laboratory. 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. One additional pathogenic variant, resulting in a different amino acid change at the same position (Arg380Cys) has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (Variation ID: 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_Moderate, PM2_Supporting, PP3_Moderate, PP2, PM5 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	5.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.97
Sift4G	Pathogenic	0.0010	D
Polyphen		0.94	P
Vest4		0.97
MutPred		0.84		Loss of MoRF binding (P = 0.0172);
MVP		0.96
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.97
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

Other links and lift over

dbSNP: rs587784498; hg19: chr6-3225184;