chr6-3154458-G-A

Variant names:

• chr6-3154458-G-A
• rs2808001
• NM_001069.3:c.743C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:2 B:1
• Conservation: PhyloP100: 9.72
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
• tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000309609 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 the TUBB2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 5.2633 (above the threshold of 3.09). Trascript score misZ: 6.0248 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 VariationId is 127101.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001069.3. 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
	TUBB2A	NM_001069.3	MANE Select	c.743C>T	p.Ala248Val	missense	Exon 4 of 4	NP_001060.1	Q13885
	TUBB2A	NM_001310315.2		c.488C>T	p.Ala163Val	missense	Exon 4 of 4	NP_001297244.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2A	ENST00000333628.4	TSL:1 MANE Select	c.743C>T	p.Ala248Val	missense	Exon 4 of 4	ENSP00000369703.2	Q13885
	TUBB2A	ENST00000940056.1		c.632C>T	p.Ala211Val	missense	Exon 3 of 3	ENSP00000610115.1
	TUBB2A	ENST00000679400.1		n.799C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 400 AN: 111804 Hom.: 0 Cov.: 16

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

GnomAD2 exomes AF: 0.0000337 AC: 8 AN: 237044 AF XY: 0.0000308

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 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: 15 AN: 1457164 Hom.: 0 Cov.: 30 AF XY: 0.00000690 AC XY: 5 AN XY: 724782

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000607 AC: 2 AN: 32928

American (AMR) AF: 0.00 AC: 0 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.000104 AC: 4 AN: 38626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5402

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110954

Other (OTH) AF: 0.00 AC: 0 AN: 60062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00360 AC: 403 AN: 111864 Hom.: 0 Cov.: 16 AF XY: 0.00361 AC XY: 191 AN XY: 52854

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0141 AC: 346 AN: 24610

American (AMR) AF: 0.00129 AC: 15 AN: 11592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3064

East Asian (EAS) AF: 0.00625 AC: 21 AN: 3358

South Asian (SAS) AF: 0.00133 AC: 4 AN: 3006

European-Finnish (FIN) AF: 0.00121 AC: 8 AN: 6616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 206

European-Non Finnish (NFE) AF: 0.0000700 AC: 4 AN: 57162

Other (OTH) AF: 0.00336 AC: 5 AN: 1488

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00211 Hom.: 0

ExAC AF: 0.000174 AC: 21

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
9	1	-	Complex cortical dysplasia with other brain malformations 5 (10)
3	-	-	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.86
Sift4G	Uncertain	0.0020	D
Polyphen		0.0080	B
Vest4		0.84
MVP		0.76
ClinPred		0.33	T
GERP RS		5.0
Varity_R		0.74
gMVP		0.96
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs2808001; hg19: chr6-3154692; COSMIC: COSV61318713; COSMIC: COSV61318713;