chr6-3225480-G-A

Variant names:

• chr6-3225480-G-A
• rs1054332
• NM_178012.5:c.609C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_178012.5(TUBB2B):​c.609C>T​(p.Asp203Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,612,216 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 30)
  • Exomes 𝑓: 0.0040 (30 hom.)
• Consequence: TUBB2B NM_178012.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.993
• Publications: 4 publications found

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]

TUBB2B Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• complex cortical dysplasia with other brain malformations 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Genomics England PanelApp
• tubulinopathy-associated dysgyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 6-3225480-G-A is Benign according to our data. Variant chr6-3225480-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.993 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0041 (623/152104) while in subpopulation NFE AF = 0.00524 (356/67924). AF 95% confidence interval is 0.00479. There are 4 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178012.5. 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
	TUBB2B	NM_178012.5	MANE Select	c.609C>T	p.Asp203Asp	synonymous	Exon 4 of 4	NP_821080.1	A0A384MEE3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2B	ENST00000259818.8	TSL:1 MANE Select	c.609C>T	p.Asp203Asp	synonymous	Exon 4 of 4	ENSP00000259818.6	Q9BVA1
	TUBB2B	ENST00000473006.1	TSL:3	n.726C>T		non_coding_transcript_exon	Exon 4 of 4
	TUBB2B	ENST00000680070.1		n.1539C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 621 AN: 151986 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00454

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00524

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.000906 AC: 224 AN: 247170 AF XY: 0.000805

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000654

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.00403 AC: 5880 AN: 1460112 Hom.: 30 Cov.: 34 AF XY: 0.00413 AC XY: 2999 AN XY: 726380

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

African (AFR) AF: 0.00270 AC: 90 AN: 33358

American (AMR) AF: 0.00264 AC: 118 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 88 AN: 26118

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.00290 AC: 250 AN: 86176

European-Finnish (FIN) AF: 0.00324 AC: 173 AN: 53376

Middle Eastern (MID) AF: 0.0254 AC: 146 AN: 5744

European-Non Finnish (NFE) AF: 0.00425 AC: 4725 AN: 1110636

Other (OTH) AF: 0.00476 AC: 287 AN: 60310

⚠️ 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: 0.00410 AC: 623 AN: 152104 Hom.: 4 Cov.: 30 AF XY: 0.00391 AC XY: 291 AN XY: 74366

African (AFR) AF: 0.00339 AC: 141 AN: 41544

American (AMR) AF: 0.00229 AC: 35 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4820

European-Finnish (FIN) AF: 0.00454 AC: 48 AN: 10566

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00524 AC: 356 AN: 67924

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00553 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Complex cortical dysplasia with other brain malformations 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.2
DANN	Benign	0.58
PhyloP100		0.99
Mutation Taster		=92/8	polymorphism

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: rs1054332; hg19: chr6-3225714;