22-18130836-C-T

Position:

• chr22-18130836-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018943.3(TUBA8):​c.1057-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,613,396 control chromosomes in the GnomAD database, including 1,418 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 0.059 (593 hom., cov: 32)
  • Exomes 𝑓: 0.022 (825 hom.)
• Consequence: TUBA8 NM_018943.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003785
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.422

Genes affected

TUBA8 (HGNC:12410): (tubulin alpha 8) This gene encodes a member of the alpha tubulin protein family. Alpha tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene are associated with polymicrogyria and optic nerve hypoplasia. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

ENSG00000288683 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 22-18130836-C-T is Benign according to our data. Variant chr22-18130836-C-T is described in ClinVar as [Benign]. Clinvar id is 137853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-18130836-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA8	NM_018943.3	c.1057-7C>T		splice_region_variant, intron_variant		ENST00000330423.8	NP_061816.1
TUBA8	NM_001193414.2	c.859-7C>T		splice_region_variant, intron_variant			NP_001180343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA8	ENST00000330423.8	c.1057-7C>T		splice_region_variant, intron_variant		1	NM_018943.3	ENSP00000333326.3
ENSG00000288683	ENST00000474897.6	n.*947-7C>T		splice_region_variant, intron_variant		5		ENSP00000434235.2

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8931 AN: 152074 Hom.: 590 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.0434

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0425

GnomAD3 exomes AF: 0.0264 AC: 6605 AN: 249958 Hom.: 256 AF XY: 0.0240 AC XY: 3243 AN XY: 135402

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.00808

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00993

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0216 AC: 31550 AN: 1461204 Hom.: 825 Cov.: 31 AF XY: 0.0208 AC XY: 15107 AN XY: 726924

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.0168

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0393

Gnomad4 NFE exome AF: 0.0183

Gnomad4 OTH exome AF: 0.0250

GnomAD4 genome AF: 0.0588 AC: 8951 AN: 152192 Hom.: 593 Cov.: 32 AF XY: 0.0573 AC XY: 4267 AN XY: 74420

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.0216

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00871

Gnomad4 FIN AF: 0.0434

Gnomad4 NFE AF: 0.0176

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0358 Hom.: 182

Bravo AF: 0.0614

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0185

EpiControl AF: 0.0171

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2013	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. -

TUBA8-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 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	-0.79
CADD	Benign	13
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.014
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: rs2234338; hg19: chr22-18613603;