6-30722634-A-G

Position:

• chr6-30722634-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_Very_Strong

The NM_178014.4(TUBB):​c.155A>G​(p.Asn52Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB NM_178014.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.17

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 Pathogenic. Variant got 11 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). 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.
• PP5: Variant 6-30722634-A-G is Pathogenic according to our data. Variant chr6-30722634-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2136013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB	NM_178014.4	c.155A>G	p.Asn52Ser	missense_variant	2/4	ENST00000327892.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB	ENST00000327892.13	c.155A>G	p.Asn52Ser	missense_variant	2/4	1	NM_178014.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32085672) -

Complex cortical dysplasia with other brain malformations 6 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Feb 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T;T
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.25
Sift4G	Benign	0.15	T;T
Polyphen		0.0	B;.
Vest4		0.64
MutPred		0.51		Loss of sheet (P = 0.1158);.;
MVP		0.82
MPC		1.5
ClinPred		0.96	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-30690411;