chr6-3225371-G-A

Variant names:

• chr6-3225371-G-A
• rs199547345
• NM_178012.5:c.718C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_178012.5(TUBB2B):​c.718C>T​(p.Leu240Leu) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,606,512 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 27)
  • Exomes 𝑓: 0.016 (203 hom.)
• Consequence: TUBB2B NM_178012.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.89
• Publications: 3 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-3225371-G-A is Benign according to our data. Variant chr6-3225371-G-A is described in ClinVar as Benign. ClinVar VariationId is 160185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0125 (1814/145128) while in subpopulation NFE AF = 0.0196 (1281/65390). AF 95% confidence interval is 0.0187. There are 15 homozygotes in GnomAd4. There are 811 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2B	NM_178012.5	MANE Select	c.718C>T	p.Leu240Leu	synonymous	Exon 4 of 4	NP_821080.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB2B	ENST00000259818.8	TSL:1 MANE Select	c.718C>T	p.Leu240Leu	synonymous	Exon 4 of 4	ENSP00000259818.6
	TUBB2B	ENST00000473006.1	TSL:3	n.835C>T		non_coding_transcript_exon	Exon 4 of 4
	TUBB2B	ENST00000680070.1		n.1648C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1815 AN: 145036 Hom.: 15 Cov.: 27

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00114

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0212

Gnomad EAS AF: 0.000423

Gnomad SAS AF: 0.00396

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0662

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0221

GnomAD2 exomes AF: 0.0119 AC: 1876 AN: 158160 AF XY: 0.0123

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00779

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.0157 AC: 23013 AN: 1461384 Hom.: 203 Cov.: 34 AF XY: 0.0158 AC XY: 11500 AN XY: 726990

African (AFR) AF: 0.00311 AC: 104 AN: 33478

American (AMR) AF: 0.00827 AC: 370 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 604 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00371 AC: 320 AN: 86248

European-Finnish (FIN) AF: 0.0134 AC: 709 AN: 53050

Middle Eastern (MID) AF: 0.0534 AC: 307 AN: 5754

European-Non Finnish (NFE) AF: 0.0177 AC: 19724 AN: 1111922

Other (OTH) AF: 0.0145 AC: 875 AN: 60384

GnomAD4 genome AF: 0.0125 AC: 1814 AN: 145128 Hom.: 15 Cov.: 27 AF XY: 0.0115 AC XY: 811 AN XY: 70220

African (AFR) AF: 0.00289 AC: 115 AN: 39820

American (AMR) AF: 0.0111 AC: 160 AN: 14466

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 71 AN: 3352

East Asian (EAS) AF: 0.000424 AC: 2 AN: 4714

South Asian (SAS) AF: 0.00397 AC: 17 AN: 4282

European-Finnish (FIN) AF: 0.0106 AC: 106 AN: 9982

Middle Eastern (MID) AF: 0.0643 AC: 18 AN: 280

European-Non Finnish (NFE) AF: 0.0196 AC: 1281 AN: 65390

Other (OTH) AF: 0.0219 AC: 43 AN: 1962

Alfa AF: 0.0159 Hom.: 2

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.46
PhyloP100		7.9
Mutation Taster		=90/10	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: rs199547345; hg19: chr6-3225605; COSMIC: COSV52534175;