rs863224939

Variant names:

• chr6-3154329-T-G
• rs863224939
• NM_001069.3:c.872A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 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:4
• Conservation: PhyloP100: 7.78
• Publications: 1 publications found

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]

TUBB2A Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
• tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000309609 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PP2: Missense variant in the TUBB2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 5.2633 (above the threshold of 3.09). Trascript score misZ: 6.0248 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 VariationId is 217024.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001069.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2A	NM_001069.3	MANE Select	c.872A>C	p.Gln291Pro	missense	Exon 4 of 4	NP_001060.1	Q13885
	TUBB2A	NM_001310315.2		c.617A>C	p.Gln206Pro	missense	Exon 4 of 4	NP_001297244.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2A	ENST00000333628.4	TSL:1 MANE Select	c.872A>C	p.Gln291Pro	missense	Exon 4 of 4	ENSP00000369703.2	Q13885
	TUBB2A	ENST00000940056.1		c.761A>C	p.Gln254Pro	missense	Exon 3 of 3	ENSP00000610115.1
	TUBB2A	ENST00000679400.1		n.928A>C		non_coding_transcript_exon	Exon 4 of 4

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

African (AFR) AF: 0.00 AC: 0 AN: 24704

American (AMR) AF: 0.00 AC: 0 AN: 33026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20068

East Asian (EAS) AF: 0.00 AC: 0 AN: 33666

South Asian (SAS) AF: 0.00 AC: 0 AN: 65384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 694522

Other (OTH) AF: 0.00 AC: 0 AN: 43168

GnomAD4 genome Cov.: 10

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Complex cortical dysplasia with other brain malformations 5 (3)
1	1	-	not provided (2)
-	1	-	Seizure (1)
-	1	-	TUBB2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.8
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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863224939; hg19: chr6-3154563;