rs878853284

Positions:

• chr6-3225373-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_178012.5(TUBB2B):​c.716G>T​(p.Cys239Phe) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 28)
• Consequence: TUBB2B NM_178012.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.98

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 Likely_pathogenic. Variant got 6 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). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. GenCC has associacion of the 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, 0.895
• PP5: Variant 6-3225373-C-A is Pathogenic according to our data. Variant chr6-3225373-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 236255.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB2B	NM_178012.5	c.716G>T	p.Cys239Phe	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.716G>T	p.Cys239Phe	missense_variant	4/4	1	NM_178012.5	ENSP00000259818.6

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 21, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.87
Sift4G	Benign	0.082	T
Polyphen		0.0090	B
Vest4		0.97
MutPred		0.69		Loss of catalytic residue at L240 (P = 0.1509);
MVP		0.70
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.98

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: rs878853284; hg19: chr6-3225607;