6-3154166-GAT-AAA

Variant names:

• chr6-3154166-GAT-AAA
• NM_001069.3:c.1033_1035delATCinsTTT
• TUBB2A p.Ile345Phe

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1_Very_Strong PP2 PP3

The NM_001069.3(TUBB2A):​c.1033_1035delATCinsTTT​(p.Ile345Phe) variant causes a missense change involving the alteration of a conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 10)
• Consequence: TUBB2A NM_001069.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.01
• Publications: 0 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, G2P, Labcorp Genetics (formerly Invitae)
• tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000309609 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_001069.3 (TUBB2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1033_1035delATCinsTTT	p.Ile345Phe	missense	N/A	NP_001060.1	Q13885
	TUBB2A	NM_001310315.2		c.778_780delATCinsTTT	p.Ile260Phe	missense	N/A	NP_001297244.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2A	ENST00000333628.4	TSL:1 MANE Select	c.1033_1035delATCinsTTT	p.Ile345Phe	missense	N/A	ENSP00000369703.2	Q13885
	TUBB2A	ENST00000940056.1		c.922_924delATCinsTTT	p.Ile308Phe	missense	N/A	ENSP00000610115.1
	TUBB2A	ENST00000679400.1		n.1089_1091delATCinsTTT		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 10

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-3154400;