chr18-12308719-C-G

Position:

• chr18-12308719-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032525.3(TUBB6):​c.90C>G​(p.Ile30Met) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBB6 NM_032525.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0660

Genes affected

TUBB6 (HGNC:20776): (tubulin beta 6 class V) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB6	NM_032525.3	c.90C>G	p.Ile30Met	missense_variant	2/4	ENST00000317702.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB6	ENST00000317702.10	c.90C>G	p.Ile30Met	missense_variant	2/4	1	NM_032525.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 18, 2019

Variant summary: TUBB6 c.90C>G (p.Ile30Met) results in a conservative amino acid change located in the Tubulin/FtsZ, GTPase domain (IPR003008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250398 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.90C>G in individuals affected with Facial Palsy, Congenital, With Ptosis and Velopharyngeal Dysfunction and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Benign	0.13	T;T;T;T;T;T;.;T
Eigen	Benign	0.093
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	5.0	.;H;.;.;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.1	.;N;.;.;.;.;.;.
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		0.68	.;P;.;.;.;.;.;.
Vest4		0.84, 0.89, 0.88, 0.87
MutPred		0.71		Loss of catalytic residue at P32 (P = 0.0407);Loss of catalytic residue at P32 (P = 0.0407);Loss of catalytic residue at P32 (P = 0.0407);Loss of catalytic residue at P32 (P = 0.0407);Loss of catalytic residue at P32 (P = 0.0407);Loss of catalytic residue at P32 (P = 0.0407);Loss of catalytic residue at P32 (P = 0.0407);Loss of catalytic residue at P32 (P = 0.0407);
MVP		0.79
MPC		1.6
ClinPred		1.0	D
GERP RS		0.81
Varity_R		0.58
gMVP		0.50

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: rs1906161383; hg19: chr18-12308718;