chr6-30721941-TCCTGGGCAACAAAGCGAGA-T

Variant names:

• chr6-30721941-TCCTGGGCAACAAAGCGAGA-T
• rs2127746598
• NM_178014.4:c.58-593_58-575delTGGGCAACAAAGCGAGACC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001293212.2(TUBB):​c.66_84delTGGGCAACAAAGCGAGACC​(p.Gly23SerfsTer10) variant causes a frameshift change involving the alteration of a non-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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBB NM_001293212.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• 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: Ambry Genetics, G2P
• 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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001293212.2. 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.58-593_58-575delTGGGCAACAAAGCGAGACC		intron	N/A	NP_821133.1	Q5SU16
	TUBB	NM_001293212.2		c.66_84delTGGGCAACAAAGCGAGACC	p.Gly23SerfsTer10	frameshift	Exon 1 of 4	NP_001280141.1
	TUBB	NM_001293214.2		c.35-974_35-956delTGGGCAACAAAGCGAGACC		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.58-593_58-575delTGGGCAACAAAGCGAGACC		intron	N/A	ENSP00000339001.7	P07437
	TUBB	ENST00000396389.5	TSL:5	c.-316_-298delTGGGCAACAAAGCGAGACC		5_prime_UTR	Exon 1 of 4	ENSP00000379672.1	Q5JP53
	TUBB	ENST00000396384.1	TSL:3	c.-430_-412delTGGGCAACAAAGCGAGACC		5_prime_UTR	Exon 1 of 4	ENSP00000379668.1	Q5ST81

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

Splicing

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

Other links and lift over

dbSNP: rs2127746598; hg19: chr6-30689718;