chr6-3225218-G-T

Variant names:

• chr6-3225218-G-T
• rs1554126886
• NM_178012.5:c.871C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM5 PP2 PP3 PP5_Very_Strong

The NM_178012.5(TUBB2B):​c.871C>A​(p.Gln291Lys) 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. Q291P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 12)
• Consequence: TUBB2B NM_178012.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-3225217-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3371508.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776
• PP5: Variant 6-3225218-G-T is Pathogenic according to our data. Variant chr6-3225218-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 437125.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	c.871C>A	p.Gln291Lys	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.871C>A	p.Gln291Lys	missense_variant	Exon 4 of 4	1	NM_178012.5	ENSP00000259818.6

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 12

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 7 Pathogenic:2

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.Gln291Lys 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. This variant was found to be de novo in 1 individual with confirmed paternity and maternity (PMID: 29671837), but was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 437125) and has been interpreted as likely pathogenic by University of Chicago Genetic Services Laboratory and University of Washington Center for Mendelian Genomics. 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. 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, PM2_Supporting, PP3, PP2 (Richards 2015). -

Nov 19, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lissencephaly Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.76
Sift4G	Uncertain	0.052	T
Polyphen		0.057	B
Vest4		0.75
MutPred		0.67		Gain of methylation at Q291 (P = 0.0102);
MVP		0.74
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.82
Mutation Taster		=7/93	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: rs1554126886; hg19: chr6-3225452;