6-30720549-C-A

Position:

• chr6-30720549-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_178014.4(TUBB):​c.43C>A​(p.Gln15Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBB NM_178014.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.78

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB. . Gene score misZ: 5.6252 (greater than the threshold 3.09). Trascript score misZ: 8.3435 (greater than threshold 3.09). The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. GenCC has associacion of the gene with multiple benign circumferential skin creases on limbs 1, complex cortical dysplasia with other brain malformations 6, multiple benign circumferential skin creases on limbs, TUBB3-related tubulinopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 6-30720549-C-A is Pathogenic according to our data. Variant chr6-30720549-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 218925.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-30720549-C-A is described in UniProt as null. Variant chr6-30720549-C-A is described in UniProt as null. Variant chr6-30720549-C-A is described in UniProt as null. Variant chr6-30720549-C-A is described in UniProt as null. Variant chr6-30720549-C-A is described in UniProt as null. Variant chr6-30720549-C-A is described in UniProt as null. Variant chr6-30720549-C-A is described in UniProt as null. Variant chr6-30720549-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB	NM_178014.4	c.43C>A	p.Gln15Lys	missense_variant	1/4	ENST00000327892.13	NP_821133.1
TUBB	NM_001293213.2	c.43C>A	p.Gln15Lys	missense_variant	1/5		NP_001280142.1
TUBB	NM_001293214.2	c.34+9C>A		intron_variant			NP_001280143.1
TUBB	NR_120608.2	n.198C>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB	ENST00000327892.13	c.43C>A	p.Gln15Lys	missense_variant	1/4	1	NM_178014.4	ENSP00000339001.7
TUBB	ENST00000681435.1	c.-159-1988C>A		intron_variant				ENSP00000506665.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Multiple benign circumferential skin creases on limbs 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.71
Sift4G	Uncertain	0.045	D
Polyphen		0.0020	B
Vest4		0.94
MutPred		0.83		Gain of methylation at Q15 (P = 0.014);
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.90
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs864321676; hg19: chr6-30688326;