6-3224861-C-T

Position:

• chr6-3224861-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_178012.5(TUBB2B):​c.1228G>A​(p.Glu410Lys) 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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: TUBB2B NM_178012.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.60

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 Pathogenic. Variant got 13 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, 0.917
• PP5: Variant 6-3224861-C-T is Pathogenic according to our data. Variant chr6-3224861-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1195195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB2B	NM_178012.5	c.1228G>A	p.Glu410Lys	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.1228G>A	p.Glu410Lys	missense_variant	4/4	1	NM_178012.5	ENSP00000259818	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 02, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TUBB2B protein function. ClinVar contains an entry for this variant (Variation ID: 1195195). This missense change has been observed in individual(s) with clinical features of tubulinopathy (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 410 of the TUBB2B protein (p.Glu410Lys). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2019	Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Tubulinopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 29, 2018

The TUBB2B c.1228G>A p.(Glu410Lys) missense variant, has not, to the best of our knowledge, been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the available evidence, the c.1228G>A p.(Glu410Lys) variant is classified as likely pathogenic for TUBB2B-related tubulinopathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.69		Gain of ubiquitination at E410 (P = 0.0114);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.81
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-3225095;