6-3224828-C-T

Position:

• chr6-3224828-C-T

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.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

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). 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, 0.853
• PP5: Variant 6-3224828-C-T is Pathogenic according to our data. Variant chr6-3224828-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88897.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-3224828-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB2B	NM_178012.5	c.1261G>A	p.Glu421Lys	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.1261G>A	p.Glu421Lys	missense_variant	4/4	1	NM_178012.5	ENSP00000259818	P1

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 2012	- -
not provided, no classification provided	literature only	GeneReviews	-	Congenital fibrosis of the extraocular muscles (CFEOM) -

Lissencephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D
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

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: rs398122369; hg19: chr6-3225062;