NM_178012.5:c.330C>T

Variant names:

• chr6-3225759-G-A
• rs141251993
• NM_178012.5:c.330C>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.330C>T​(p.Ala110Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00711 in 1,613,012 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (66 hom.)
• Consequence: TUBB2B NM_178012.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.48
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-3225759-G-A is Benign according to our data. Variant chr6-3225759-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00565 (859/152060) while in subpopulation SAS AF = 0.00958 (46/4800). AF 95% confidence interval is 0.00738. There are 5 homozygotes in GnomAd4. There are 417 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.330C>T	p.Ala110Ala	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.330C>T	p.Ala110Ala	synonymous	Exon 4 of 4	ENSP00000259818.6
	TUBB2B	ENST00000473006.1	TSL:3	n.447C>T		non_coding_transcript_exon	Exon 4 of 4
	TUBB2B	ENST00000680070.1		n.1260C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00564 AC: 857 AN: 151942 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00916

Gnomad FIN AF: 0.00736

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00742

Gnomad OTH AF: 0.00817

GnomAD2 exomes AF: 0.00747 AC: 1853 AN: 248162 AF XY: 0.00800

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.00491

Gnomad ASJ exome AF: 0.00550

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00866

Gnomad NFE exome AF: 0.00930

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.00726 AC: 10607 AN: 1460952 Hom.: 66 Cov.: 34 AF XY: 0.00761 AC XY: 5531 AN XY: 726734

African (AFR) AF: 0.00152 AC: 51 AN: 33460

American (AMR) AF: 0.00477 AC: 213 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00517 AC: 135 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0110 AC: 945 AN: 86170

European-Finnish (FIN) AF: 0.00727 AC: 386 AN: 53112

Middle Eastern (MID) AF: 0.0196 AC: 112 AN: 5708

European-Non Finnish (NFE) AF: 0.00747 AC: 8299 AN: 1111700

Other (OTH) AF: 0.00771 AC: 465 AN: 60338

GnomAD4 genome AF: 0.00565 AC: 859 AN: 152060 Hom.: 5 Cov.: 31 AF XY: 0.00561 AC XY: 417 AN XY: 74324

African (AFR) AF: 0.00152 AC: 63 AN: 41508

American (AMR) AF: 0.00766 AC: 117 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00664 AC: 23 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00958 AC: 46 AN: 4800

European-Finnish (FIN) AF: 0.00736 AC: 78 AN: 10598

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00742 AC: 504 AN: 67956

Other (OTH) AF: 0.00808 AC: 17 AN: 2104

Alfa AF: 0.00708 Hom.: 3

Bravo AF: 0.00546

EpiCase AF: 0.0105

EpiControl AF: 0.0111

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.053
DANN	Benign	0.58
PhyloP100		-2.5
Mutation Taster		=99/1	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: rs141251993; hg19: chr6-3225993;