chr6-3224828-C-T

Variant names:

• chr6-3224828-C-T
• rs398122369
• NM_178012.5:c.1261G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_178012.5(TUBB2B):​c.1261G>A​(p.Glu421Lys) 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 (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TUBB2B NM_178012.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 7.64
• Publications: 13 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 6 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 6-3224828-C-T is Pathogenic according to our data. Variant chr6-3224828-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 88897.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178012.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2B	NM_178012.5	MANE Select	c.1261G>A	p.Glu421Lys	missense	Exon 4 of 4	NP_821080.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2B	ENST00000259818.8	TSL:1 MANE Select	c.1261G>A	p.Glu421Lys	missense	Exon 4 of 4	ENSP00000259818.6
	TUBB2B	ENST00000473006.1	TSL:3	n.1378G>A		non_coding_transcript_exon	Exon 4 of 4
	TUBB2B	ENST00000680070.1		n.2191G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 7 Pathogenic:1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Congenital fibrosis of the extraocular muscles (CFEOM)

Dec 15, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.030	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.63
Sift4G	Uncertain	0.030	D
Polyphen		0.13	B
Vest4		0.94
MutPred		0.55		Gain of methylation at E421 (P = 0.0035)
MVP		0.71
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.75
gMVP		1.0
Mutation Taster		=10/90	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: rs398122369; hg19: chr6-3225062;