rs1483521190

Variant names:

• chr6-3224893-G-A
• rs1483521190
• NM_178012.5:c.1196C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_178012.5(TUBB2B):​c.1196C>T​(p.Thr399Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,600,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TUBB2B NM_178012.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• Publications: 1 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 congenital fibrosis of extraocular muscles, tubulinopathy-associated dysgyria, 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, 0.877

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.1196C>T	p.Thr399Met	missense	Exon 4 of 4	NP_821080.1	A0A384MEE3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2B	ENST00000259818.8	TSL:1 MANE Select	c.1196C>T	p.Thr399Met	missense	Exon 4 of 4	ENSP00000259818.6	Q9BVA1
	TUBB2B	ENST00000473006.1	TSL:3	n.1313C>T		non_coding_transcript_exon	Exon 4 of 4
	TUBB2B	ENST00000680070.1		n.2126C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00000696 AC: 1 AN: 143754 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246536 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456940 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724674

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4600

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110664

Other (OTH) AF: 0.00 AC: 0 AN: 60212

GnomAD4 genome AF: 0.00000696 AC: 1 AN: 143754 Hom.: 0 Cov.: 21 AF XY: 0.0000144 AC XY: 1 AN XY: 69470

African (AFR) AF: 0.00 AC: 0 AN: 38200

American (AMR) AF: 0.00 AC: 0 AN: 14088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 4904

South Asian (SAS) AF: 0.00 AC: 0 AN: 4174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66164

Other (OTH) AF: 0.00 AC: 0 AN: 1882

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.66
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.53		Gain of catalytic residue at T399 (P = 0.034)
MVP		0.90
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.58
gMVP		0.87
Mutation Taster		=14/86	disease causing

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: rs1483521190; hg19: chr6-3225127;