chr6-30721970-A-T

Variant names:

• chr6-30721970-A-T
• rs369813241
• NM_178014.4:c.58-567A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001293212.2(TUBB):​c.92A>T​(p.His31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H31R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB NM_001293212.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388
• 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_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: 8.0682 (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.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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.58-567A>T		intron	N/A	NP_821133.1	Q5SU16
	TUBB	NM_001293212.2		c.92A>T	p.His31Leu	missense	Exon 1 of 4	NP_001280141.1
	TUBB	NM_001293214.2		c.35-948A>T		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.58-567A>T		intron	N/A	ENSP00000339001.7	P07437
	TUBB	ENST00000396389.5	TSL:5	c.-290A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000379672.1	Q5JP53
	TUBB	ENST00000396384.1	TSL:3	c.-404A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000379668.1	Q5ST81

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 9

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.2
DANN	Benign	0.31
PhyloP100		-0.39
PromoterAI		-0.021	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs369813241; hg19: chr6-30689747;