18-12308794-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032525.3(TUBB6):c.165G>C(p.Ser55=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,592,370 control chromosomes in the GnomAD database, including 10,387 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (943 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9444 hom.)
• Consequence: TUBB6 NM_032525.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003294
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.04

Genes affected

TUBB6 (HGNC:20776): (tubulin beta 6 class V) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 18-12308794-G-C is Benign according to our data. Variant chr18-12308794-G-C is described in ClinVar as [Benign]. Clinvar id is 1684209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB6	NM_032525.3	c.165G>C	p.Ser55=	splice_region_variant, synonymous_variant	2/4	ENST00000317702.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB6	ENST00000317702.10	c.165G>C	p.Ser55=	splice_region_variant, synonymous_variant	2/4	1	NM_032525.3	P1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16687 AN: 152120 Hom.: 944 Cov.: 33

Gnomad AFR AF: 0.0822

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0850

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.126 AC: 31297 AN: 248668 Hom.: 2101 AF XY: 0.126 AC XY: 16962 AN XY: 134956

Gnomad AFR exome AF: 0.0806

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.157

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0896

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.111 AC: 159369 AN: 1440132 Hom.: 9444 Cov.: 27 AF XY: 0.112 AC XY: 80498 AN XY: 717752

Gnomad4 AFR exome AF: 0.0785

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.0922

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.110 AC: 16689 AN: 152238 Hom.: 943 Cov.: 33 AF XY: 0.110 AC XY: 8196 AN XY: 74438

Gnomad4 AFR AF: 0.0821

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.0850

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.130

Alfa AF: 0.0915 Hom.: 261

Bravo AF: 0.114

EpiCase AF: 0.131

EpiControl AF: 0.129

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Facial palsy, congenital, with ptosis and velopharyngeal dysfunction Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

TUBB6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	11
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.010
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: rs11267036; hg19: chr18-12308793; COSMIC: COSV58353184; COSMIC: COSV58353184;