rs2259136

Variant names:

• chr6-3225525-C-A
• rs2259136
• NM_178012.5:c.564G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-3225525-C-A
• chr6-3225525-C-T
• chr6-3225525-C-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_178012.5(TUBB2B):​c.564G>T​(p.Ser188Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,570,210 control chromosomes in the GnomAD database, including 1,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S188S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.052 (244 hom., cov: 31)
  • Exomes 𝑓: 0.017 (1292 hom.)
• Consequence: TUBB2B NM_178012.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.28
• Publications: 7 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=-0.77).
• BP6: Variant 6-3225525-C-A is Benign according to our data. Variant chr6-3225525-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

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.564G>T	p.Ser188Ser	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.564G>T	p.Ser188Ser	synonymous	Exon 4 of 4	ENSP00000259818.6	Q9BVA1
	TUBB2B	ENST00000473006.1	TSL:3	n.681G>T		non_coding_transcript_exon	Exon 4 of 4
	TUBB2B	ENST00000680070.1		n.1494G>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0523 AC: 7173 AN: 137108 Hom.: 243 Cov.: 31

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.00434

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.0606

Gnomad FIN AF: 0.00841

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0404 AC: 9283 AN: 230044 AF XY: 0.0346

Gnomad AFR exome AF: 0.0911

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.00221

Gnomad EAS exome AF: 0.205

Gnomad FIN exome AF: 0.00507

Gnomad NFE exome AF: 0.000813

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0172 AC: 24641 AN: 1433012 Hom.: 1292 Cov.: 34 AF XY: 0.0172 AC XY: 12263 AN XY: 712252

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

African (AFR) AF: 0.0988 AC: 2261 AN: 22890

American (AMR) AF: 0.173 AC: 7390 AN: 42806

Ashkenazi Jewish (ASJ) AF: 0.00299 AC: 78 AN: 26070

East Asian (EAS) AF: 0.214 AC: 7844 AN: 36632

South Asian (SAS) AF: 0.0519 AC: 4113 AN: 79268

European-Finnish (FIN) AF: 0.00763 AC: 394 AN: 51614

Middle Eastern (MID) AF: 0.0154 AC: 85 AN: 5530

European-Non Finnish (NFE) AF: 0.000982 AC: 1090 AN: 1109902

Other (OTH) AF: 0.0238 AC: 1386 AN: 58300

⚠️ 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: 0.0524 AC: 7190 AN: 137198 Hom.: 244 Cov.: 31 AF XY: 0.0569 AC XY: 3813 AN XY: 66976

African (AFR) AF: 0.131 AC: 3773 AN: 28844

American (AMR) AF: 0.120 AC: 1745 AN: 14600

Ashkenazi Jewish (ASJ) AF: 0.00434 AC: 15 AN: 3456

East Asian (EAS) AF: 0.233 AC: 1091 AN: 4680

South Asian (SAS) AF: 0.0598 AC: 269 AN: 4498

European-Finnish (FIN) AF: 0.00841 AC: 86 AN: 10220

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 67756

Other (OTH) AF: 0.0418 AC: 81 AN: 1940

Alfa AF: 0.00706 Hom.: 5

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.20
DANN	Benign	0.65
PhyloP100		-5.3
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2259136; hg19: chr6-3225759; COSMIC: COSV52534604;