6-30720549-CAG-AAA

Variant names:

• chr6-30720549-CAG-AAA
• NM_178014.4:c.43_45delCAGinsAAA
• TUBB p.Gln15Lys

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM5 PP2 PP3

The NM_178014.4(TUBB):​c.43_45delCAGinsAAA​(p.Gln15Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q15H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB NM_178014.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.18
• Publications: 0 publications found

Genes affected

TUBB (HGNC:20778): (tubulin beta class I) This gene encodes a beta tubulin protein. This protein forms a dimer with alpha tubulin and acts as a structural component of microtubules. Mutations in this gene cause cortical dysplasia, complex, with other brain malformations 6. Alternative splicing results in multiple splice variants. There are multiple pseudogenes for this gene on chromosomes 1, 6, 7, 8, 9, and 13. [provided by RefSeq, Jun 2014]

TUBB Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations 6

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• multiple benign circumferential skin creases on limbs 1

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
• TUBB3-related tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• multiple benign circumferential skin creases on limbs

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_178014.4 (TUBB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-30720551-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1685467.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the TUBB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 5.6252 (above the threshold of 3.09). Trascript score misZ: 8.3435 (above the threshold of 3.09). GenCC associations: The gene is linked to complex cortical dysplasia with other brain malformations 6, multiple benign circumferential skin creases on limbs, multiple benign circumferential skin creases on limbs 1, TUBB3-related 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_178014.4. 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
	TUBB	NM_178014.4	MANE Select	c.43_45delCAGinsAAA	p.Gln15Lys	missense	N/A	NP_821133.1	Q5SU16
	TUBB	NM_001293213.2		c.43_45delCAGinsAAA	p.Gln15Lys	missense	N/A	NP_001280142.1	B4DMJ5
	TUBB	NM_001293214.2		c.34+9_34+11delCAGinsAAA		intron	N/A	NP_001280143.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB	ENST00000327892.13	TSL:1 MANE Select	c.43_45delCAGinsAAA	p.Gln15Lys	missense	N/A	ENSP00000339001.7	P07437
	TUBB	ENST00000940307.1		c.43_45delCAGinsAAA	p.Gln15Lys	missense	N/A	ENSP00000610366.1
	TUBB	ENST00000940306.1		c.43_45delCAGinsAAA	p.Gln15Lys	missense	N/A	ENSP00000610365.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

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: chr6-30688326;