rs1554202416

Positions:

• chr6-30723922-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The ENST00000327892.13(TUBB):​c.860C>T​(p.Pro287Leu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P287S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB ENST00000327892.13 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 7.63

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-30723921-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2662647.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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). GenCC has associacion of 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, 0.913
• PP5: Variant 6-30723922-C-T is Pathogenic according to our data. Variant chr6-30723922-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438586.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB	NM_178014.4	c.860C>T	p.Pro287Leu	missense_variant	4/4	ENST00000327892.13	NP_821133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB	ENST00000327892.13	c.860C>T	p.Pro287Leu	missense_variant	4/4	1	NM_178014.4	ENSP00000339001	P1
	ENST00000607476.1			upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 6 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Sep 01, 2017	this variant was indentified in an individual with malformations of cortical development -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2022	- -

Multiple benign circumferential skin creases on limbs 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2022

- -

Lissencephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29706646, 35586607, 36305856, 29261186, 29671837) -

Seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Nov 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.;D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.4	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.0	D;D;D;D
REVEL	Pathogenic	0.74
Sift4G	Uncertain	0.037	D;D;D;D
Polyphen		0.50	P;.;.;.
Vest4		0.80
MutPred		0.58		Loss of disorder (P = 0.1466);.;.;.;
MVP		0.98
MPC		2.7
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.98

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: rs1554202416; hg19: chr6-30691699;