6-3154458-G-A

Position:

chr6-3154458-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP2PP5

The NM_001069.3(TUBB2A):c.743C>T(p.Ala248Val) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 0 hom., cov: 16)

Exomes 𝑓: 0.000010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TUBB2A
NM_001069.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:2B:1

Conservation

PhyloP100: 9.72

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001069.3

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB2A. . Gene score misZ 5.2633 (greater than the threshold 3.09). Trascript score misZ 6.0248 (greater than threshold 3.09). GenCC has associacion of gene with complex cortical dysplasia with other brain malformations 5, tubulinopathy.

PP5

Variant 6-3154458-G-A is Pathogenic according to our data. Variant chr6-3154458-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127101.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Likely_benign=1, Likely_pathogenic=2, Uncertain_significance=2}. Variant chr6-3154458-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB2A	NM_001069.3 linkuse as main transcript	c.743C>T	p.Ala248Val	missense_variant	4/4	ENST00000333628.4
TUBB2A	NM_001310315.2 linkuse as main transcript	c.488C>T	p.Ala163Val	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB2A	ENST00000333628.4 linkuse as main transcript	c.743C>T	p.Ala248Val	missense_variant	4/4	1	NM_001069.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

400

AN:

111804

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00130

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00654

Gnomad SAS

AF:

0.00133

Gnomad FIN

AF:

0.00121

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000700

Gnomad OTH

AF:

0.00338

GnomAD3 exomes

AF:

0.0000337

AC:

AN:

237044

Hom.:

AF XY:

0.0000308

AC XY:

AN XY:

129760

show subpopulations

Gnomad AFR exome

AF:

0.000142

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.000100

Gnomad FIN exome

AF:

0.0000477

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000103

AC:

AN:

1457164

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724782

show subpopulations

Gnomad4 AFR exome

AF:

0.0000607

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000104

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00360

AC:

403

AN:

111864

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

191

AN XY:

52854

show subpopulations

Gnomad4 AFR

AF:

0.0141

Gnomad4 AMR

AF:

0.00129

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00625

Gnomad4 SAS

AF:

0.00133

Gnomad4 FIN

AF:

0.00121

Gnomad4 NFE

AF:

0.0000700

Gnomad4 OTH

AF:

0.00336

Alfa

AF:

0.00211

Hom.:

ExAC

AF:

0.000174

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 5

Pathogenic:7Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 27, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 25, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with cortical dysplasia, complex, with other brain malformations 5, (MIM#615763). Functional studies have shown missense variants to cause weakened incorporation into cytoskeleton, and potentially impaired heterodimer formation indicating loss of function. However, the mutational spectrum is more suggestive of a dominant negative mechanism (PMID: 24702957). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (400 heterozygotes, 0 homozygotes). However, most of these are likely sequencing artefacts. The remaining were observed in individuals with a neurodevelopmental disorder (PMID: 33547136). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once each as a VUS and likely benign; however, the majority of submissions are pathogenic and likely pathogenic (ClinVar). It has also been observed multiple times as de novo in individuals with simplified gyral patterning and infantile-onset epilepsy (PMID: 24702957, PMID: 32203252). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 11, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Jan 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2021	Published functional studies demonstrate that this variant has a reduced rate of heterodimer incorporation into the in vitro cytoskeleton network in comparison with wild type-expressing cells (Cushion et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26934450, 24702957, 27770045, 32203252, 32571897) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 248 of the TUBB2A protein (p.Ala248Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with TUBB2A-related conditions (PMID: 24702957, 27770045, 32203252, 32571897; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127101). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TUBB2A protein function. Experimental studies have shown that this missense change affects TUBB2A function (PMID: 24702957, 29547997). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2021

The c.743C>T (p.A248V) alteration is located in exon 4 (coding exon 4) of the TUBB2A gene. This alteration results from a C to T substitution at nucleotide position 743, causing the alanine (A) at amino acid position 248 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD) database, the TUBB2A c.743C>T alteration was observed in 0.03% (87/252926) of total alleles studied, with a frequency of 0.37% (68/18432) in the African subpopulation; however, this data may be an unreliable mismapping artefact (Ragoussis, 2021). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Apr 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.86

Sift4G

Uncertain

0.0020

Polyphen

0.0080

Vest4

0.84

MVP

0.76

ClinPred

0.33

GERP RS

5.0

Varity_R

0.74

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over