6-3224917-C-T

Position:

• chr6-3224917-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5 PP2 PP3 PP5_Very_Strong

The ENST00000259818.8(TUBB2B):​c.1172G>A​(p.Arg391His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBB2B ENST00000259818.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.82

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 Pathogenic. Variant got 12 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-3224918-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2578313.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB2B. . Gene score misZ 5.1195 (greater than the threshold 3.09). Trascript score misZ 6.9522 (greater than threshold 3.09). GenCC has associacion of gene with tubulinopathy-associated dysgyria, congenital fibrosis of extraocular muscles, cerebellar ataxia, intellectual disability, and dysequilibrium, complex cortical dysplasia with other brain malformations 7, complex cortical dysplasia with other brain malformations.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• PP5: Variant 6-3224917-C-T is Pathogenic according to our data. Variant chr6-3224917-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 809861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB2B	NM_178012.5	c.1172G>A	p.Arg391His	missense_variant	4/4	ENST00000259818.8	NP_821080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB2B	ENST00000259818.8	c.1172G>A	p.Arg391His	missense_variant	4/4	1	NM_178012.5	ENSP00000259818	P1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1449816 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720620

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.: 20

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences

Aug 03, 2022

The missense variant NM_178012.5(TUBB2B):c.1172G>A (p.Arg391His) causes the same amino acid change as a previously established pathogenic variant. The p.Arg391His variant is novel (not in any individuals) in 1kG All. The p.Arg391His variant is novel (not in any individuals) in gnomAD as well as in our inhouse database. The variant was previously reported in ClinVar as Likely Pathogenic (Accession:VCV000809861.14). There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene TUBB2B has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 5.12. The gene TUBB2B contains 31 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. 3 variants within 6 amino acid positions of the variant p.Arg391His have been shown to be pathogenic, while none have been shown to be benign. In addition, the clinical phenotype of the proband matches with that of the disorder caused by pathogenic variants in the TUBB2B gene. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.83
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.86		Loss of MoRF binding (P = 0.0209);
MVP		0.89
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.74
gMVP		0.92

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: rs1581525683; hg19: chr6-3225151; COSMIC: COSV52534660;