rs201922441

Variant names:

• chr6-3225487-C-A
• rs201922441
• NM_178012.5:c.602G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-3225487-C-A
• chr6-3225487-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_Moderate

The NM_178012.5(TUBB2B):​c.602G>T​(p.Cys201Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C201S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TUBB2B NM_178012.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.973
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• complex cortical dysplasia with other brain malformations 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Genomics England PanelApp
• tubulinopathy-associated dysgyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_178012.5
• PM2: Very rare variant in population databases, with high coverage
• 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, complex cortical dysplasia with other brain malformations 7, complex cortical dysplasia with other brain malformations, cerebellar ataxia, intellectual disability, and dysequilibrium.
• PP5: Variant 6-3225487-C-A is Pathogenic according to our data. Variant chr6-3225487-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 864868.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB2B	NM_178012.5	c.602G>T	p.Cys201Phe	missense_variant	Exon 4 of 4	ENST00000259818.8	NP_821080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB2B	ENST00000259818.8	c.602G>T	p.Cys201Phe	missense_variant	Exon 4 of 4	1	NM_178012.5	ENSP00000259818.6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 7 Pathogenic:1

Jan 01, 2020

Bruce Lefroy Centre, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PM6, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		0.97
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Uncertain	0.35
Sift4G	Pathogenic	0.0010	D
Polyphen		0.77	P
Vest4		0.49
MutPred		0.31		Loss of catalytic residue at E198 (P = 0.2465);
MVP		0.82
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.92
gMVP		0.99
Mutation Taster		=84/16	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs201922441; hg19: chr6-3225721;