6-3225361-G-T

Variant names:

• chr6-3225361-G-T
• rs1554126902
• NM_178012.5:c.728C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_178012.5(TUBB2B):​c.728C>A​(p.Pro243Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P243L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 26)
• Consequence: TUBB2B NM_178012.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.73
• Publications: 0 publications found

Genes affected

TUBB2B (HGNC:30829): (tubulin beta 2B class IIb) The protein encoded by this gene is a beta isoform of tubulin, which binds GTP and is a major component of microtubules. This gene is highly similar to TUBB2A and TUBB2C. Defects in this gene are a cause of asymmetric polymicrogyria. [provided by RefSeq, Mar 2010]

TUBB2B Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• complex cortical dysplasia with other brain malformations 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Genomics England PanelApp
• tubulinopathy-associated dysgyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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 1 benign, 5 uncertain in NM_178012.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-3225361-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 495257.
• PP2: Missense variant in the TUBB2B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 5.1195 (above the threshold of 3.09). Trascript score misZ: 6.9522 (above the threshold of 3.09). GenCC associations: The gene is linked to tubulinopathy-associated dysgyria, congenital fibrosis of extraocular muscles, complex cortical dysplasia with other brain malformations 7, complex cortical dysplasia with other brain malformations, cerebellar ataxia, intellectual disability, and dysequilibrium.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178012.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2B	NM_178012.5	MANE Select	c.728C>A	p.Pro243Gln	missense	Exon 4 of 4	NP_821080.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2B	ENST00000259818.8	TSL:1 MANE Select	c.728C>A	p.Pro243Gln	missense	Exon 4 of 4	ENSP00000259818.6
	TUBB2B	ENST00000473006.1	TSL:3	n.845C>A		non_coding_transcript_exon	Exon 4 of 4
	TUBB2B	ENST00000680070.1		n.1658C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Benign	0.95
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.86
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.78
MutPred		0.86		Loss of methylation at R241 (P = 0.1223)
MVP		0.73
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.90
gMVP		0.86
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554126902; hg19: chr6-3225595;