6-3154329-T-G

Position:

• chr6-3154329-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP2 PP3_Strong PP5

The NM_001069.3(TUBB2A):​c.872A>C​(p.Gln291Pro) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 10)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB2A NM_001069.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 7.78

Genes affected

TUBB2A (HGNC:12412): (tubulin beta 2A class IIa) Microtubules, key participants in processes such as mitosis and intracellular transport, are composed of heterodimers of alpha- and beta-tubulins. The protein encoded by this gene is a beta-tubulin. Defects in this gene are associated with complex cortical dysplasia with other brain malformations-5. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB2A. . Gene score misZ 5.2633 (greater than the threshold 3.09). Trascript score misZ 6.0248 (greater than threshold 3.09). GenCC has associacion of gene with complex cortical dysplasia with other brain malformations 5, tubulinopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 6-3154329-T-G is Pathogenic according to our data. Variant chr6-3154329-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217024.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB2A	NM_001069.3	c.872A>C	p.Gln291Pro	missense_variant	4/4	ENST00000333628.4
TUBB2A	NM_001310315.2	c.617A>C	p.Gln206Pro	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB2A	ENST00000333628.4	c.872A>C	p.Gln291Pro	missense_variant	4/4	1	NM_001069.3	P1

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 950868 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 477354

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 5 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 10, 2022	ACMG classification criteria: PS4 supporting, PM2 moderate, PM6, PP3 supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Jan 28, 2014	- -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2022	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28840640, 32203252, 31589614, 25326637) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 23, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 TUBB2A protein function. ClinVar contains an entry for this variant (Variation ID: 217024). This missense change has been observed in individual(s) with TUBB2A-related conditions (PMID: 25326637). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 291 of the TUBB2A protein (p.Gln291Pro). -

TUBB2A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 12, 2023

The TUBB2A c.872A>C variant is predicted to result in the amino acid substitution p.Gln291Pro. This variant was reported to have occurred de novo in an individual with developmental delay, short stature, seizures, ureteropelvic junction obstruction, constipation, hydronephrosis, clinodactyly, growth hormone deficiency, and Russell Silver syndrome (Lee et al. 2014. PubMed ID: 25326637, eTable 2). This variant was also reported in a presumably unaffected gamete donor in a large carrier screening study (Capalbo A et al 2019. PubMed ID: 31589614, supplemental table S1). At PreventionGenetics, we detected this variant in an individual with a neurodevelopmental phenotype, but it was inherited from a presumably unaffected parent (internal data). This variant has not been reported in a large population database, indicating it is rare. Although we suspect this variant may be pathogenic, at this time the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Seizure Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.93
Sift4G	Uncertain	0.0030	D
Polyphen		0.78	P
Vest4		0.80
MutPred		0.74		Gain of phosphorylation at T290 (P = 0.096);
MVP		0.96
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863224939; hg19: chr6-3154563;