rs141251993

Positions:

• chr6-3225759-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 160180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-3225759-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00726 (10607/1460952) while in subpopulation MID AF= 0.0196 (112/5708). AF 95% confidence interval is 0.0167. There are 66 homozygotes in gnomad4_exome. There are 5531 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 859 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB2B	NM_178012.5	c.330C>T	p.Ala110Ala	synonymous_variant	4/4	ENST00000259818.8	NP_821080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB2B	ENST00000259818.8	c.330C>T	p.Ala110Ala	synonymous_variant	4/4	1	NM_178012.5	ENSP00000259818.6

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

GnomAD3 exomes AF: 0.00747 AC: 1853 AN: 248162 Hom.: 5 AF XY: 0.00800 AC XY: 1079 AN XY: 134904

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 SAS exome AF: 0.0106

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

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00477

Gnomad4 ASJ exome AF: 0.00517

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.00727

Gnomad4 NFE exome AF: 0.00747

Gnomad4 OTH exome AF: 0.00771

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

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00766

Gnomad4 ASJ AF: 0.00664

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00958

Gnomad4 FIN AF: 0.00736

Gnomad4 NFE AF: 0.00742

Gnomad4 OTH AF: 0.00808

Alfa AF: 0.00708 Hom.: 3

Bravo AF: 0.00546

EpiCase AF: 0.0105

EpiControl AF: 0.0111

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 24, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TUBB2B: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.053
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs141251993; hg19: chr6-3225993;