6-3224950-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5 PP2 PP3_Moderate PP5

The NM_178012.5(TUBB2B):c.1139G>A(p.Arg380His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R380C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB2B NM_178012.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-3224951-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1214258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TUBB2B
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 6-3224950-C-T is Pathogenic according to our data. Variant chr6-3224950-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2498169.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB2B	NM_178012.5	c.1139G>A	p.Arg380His	missense_variant	4/4	ENST00000259818.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB2B	ENST00000259818.8	c.1139G>A	p.Arg380His	missense_variant	4/4	1	NM_178012.5	P1

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD3 exomes AF: 0.00000457 AC: 1 AN: 218848 Hom.: 0 AF XY: 0.00000830 AC XY: 1 AN XY: 120550

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1410766 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 699474

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 7 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	Mar 23, 2023	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 22, 2024	The heterozygous p.Arg380His variant in TUBB2B was identified by our study in one individual with cortical dysplasia, complex, with other brain malformations 7. Trio exome analysis showed this variant to be de novo. The variant has not been previously reported in individuals with cortical dysplasia, complex, with other brain malformations 7 and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 2498169) and has been interpreted as uncertain significance by Invitae and likely pathogenic by Oxford Medical Genetics Laboratories. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in TUBB2B in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Two additional likely pathogenic and pathogenic variants, resulting in a different amino acid change at the same position, (p.Arg380Leu and Arg380Cys), have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (Variation IDs: 160177, 1214258). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant cortical dysplasia, complex, with other brain malformations 7. ACMG/AMP Criteria applied: PS2_Supporting, PM2_Supporting, PP3_Moderate, PP2, PM5 (Richards 2015). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 13, 2023

This variant disrupts the p.Arg380 amino acid residue in TUBB2B. Other variant(s) that disrupt this residue have been observed in individuals with TUBB2B-related conditions (PMID: 25140959, 31481326), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 380 of the TUBB2B protein (p.Arg380His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cortical brain malformations (Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TUBB2B protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.81
Sift4G	Uncertain	0.048	D
Polyphen		0.25	B
Vest4		0.78
MutPred		0.78		Loss of MoRF binding (P = 0.0193);
MVP		0.78
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.82
gMVP		0.95

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: rs587784498; hg19: chr6-3225184;