chr6-3154460-G-C

Variant names:

• chr6-3154460-G-C
• rs886037663
• NM_001069.3:c.741C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001069.3(TUBB2A):​c.741C>G​(p.Asn247Lys) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 17)
• Consequence: TUBB2A NM_001069.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: -0.368
• Publications: 2 publications found

Genes affected

TUBB2A (HGNC:12412): (tubulin beta 2A class IIa) Microtubules, key participants in processes such as mitosis and intracellular transport, are composed of heterodimers of alpha- and beta-tubulins. The protein encoded by this gene is a beta-tubulin. Defects in this gene are associated with complex cortical dysplasia with other brain malformations-5. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

TUBB2A Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
• tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000309609 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001069.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TUBB2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 5.2633 (above the threshold of 3.09). Trascript score misZ: 6.0248 (above the threshold of 3.09). GenCC associations: The gene is linked to complex cortical dysplasia with other brain malformations 5, tubulinopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 6-3154460-G-C is Pathogenic according to our data. Variant chr6-3154460-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 127100.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001069.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2A	NM_001069.3	MANE Select	c.741C>G	p.Asn247Lys	missense	Exon 4 of 4	NP_001060.1
	TUBB2A	NM_001310315.2		c.486C>G	p.Asn162Lys	missense	Exon 4 of 4	NP_001297244.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2A	ENST00000333628.4	TSL:1 MANE Select	c.741C>G	p.Asn247Lys	missense	Exon 4 of 4	ENSP00000369703.2
	TUBB2A	ENST00000679400.1		n.797C>G		non_coding_transcript_exon	Exon 4 of 4
	TUBB2A	ENST00000679907.1		n.1129C>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 17

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 5 Pathogenic:2

Feb 04, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 03, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Congenital cerebellar hypoplasia Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		-0.37
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.88
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.88		Loss of ubiquitination at K252 (P = 0.0426)
MVP		0.86
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.83
gMVP		0.99
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs886037663; hg19: chr6-3154694;