chr6-3154637-A-C

Variant names:

• chr6-3154637-A-C
• rs17849443
• NM_001069.3:c.564T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001069.3(TUBB2A):​c.564T>G​(p.Ser188Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,606,018 control chromosomes in the GnomAD database, including 335,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23834 hom., cov: 28)
  • Exomes 𝑓: 0.65 (311966 hom.)
• Consequence: TUBB2A NM_001069.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.57
• Publications: 13 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 6-3154637-A-C is Benign according to our data. Variant chr6-3154637-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 378835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

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.564T>G	p.Ser188Ser	synonymous	Exon 4 of 4	NP_001060.1	Q13885
	TUBB2A	NM_001310315.2		c.309T>G	p.Ser103Ser	synonymous	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.564T>G	p.Ser188Ser	synonymous	Exon 4 of 4	ENSP00000369703.2	Q13885
	TUBB2A	ENST00000940056.1		c.453T>G	p.Ser151Ser	synonymous	Exon 3 of 3	ENSP00000610115.1
	TUBB2A	ENST00000489942.1	TSL:2	n.759T>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.534 AC: 80309 AN: 150276 Hom.: 23832 Cov.: 28

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.559

GnomAD2 exomes AF: 0.555 AC: 138291 AN: 249096 AF XY: 0.563

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.422

Gnomad FIN exome AF: 0.644

Gnomad NFE exome AF: 0.687

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.647 AC: 941220 AN: 1455628 Hom.: 311966 Cov.: 141 AF XY: 0.642 AC XY: 464630 AN XY: 724272

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

African (AFR) AF: 0.241 AC: 7918 AN: 32824

American (AMR) AF: 0.408 AC: 17648 AN: 43266

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 15649 AN: 26092

East Asian (EAS) AF: 0.422 AC: 16335 AN: 38726

South Asian (SAS) AF: 0.408 AC: 34859 AN: 85506

European-Finnish (FIN) AF: 0.662 AC: 35232 AN: 53254

Middle Eastern (MID) AF: 0.510 AC: 2902 AN: 5690

European-Non Finnish (NFE) AF: 0.697 AC: 773763 AN: 1110202

Other (OTH) AF: 0.615 AC: 36914 AN: 60068

⚠️ 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 AF: 0.534 AC: 80330 AN: 150390 Hom.: 23834 Cov.: 28 AF XY: 0.531 AC XY: 38964 AN XY: 73372

African (AFR) AF: 0.270 AC: 11076 AN: 41062

American (AMR) AF: 0.484 AC: 7271 AN: 15026

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2107 AN: 3454

East Asian (EAS) AF: 0.442 AC: 2209 AN: 4994

South Asian (SAS) AF: 0.402 AC: 1897 AN: 4724

European-Finnish (FIN) AF: 0.668 AC: 6932 AN: 10378

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.695 AC: 46889 AN: 67460

Other (OTH) AF: 0.561 AC: 1172 AN: 2090

Alfa AF: 0.548 Hom.: 2912

Bravo AF: 0.513

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Complex cortical dysplasia with other brain malformations 5 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.090
DANN	Benign	0.56
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs17849443; hg19: chr6-3154871; COSMIC: COSV61319049; COSMIC: COSV61319049;