rs2234331

chr22-18126361-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_018943.3(TUBA8):c.383C>T(p.Ala128Val) variant causes a missense change. The variant allele was found at a frequency of 0.0108 in 1,614,118 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0075 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (119 hom.)
• Consequence: TUBA8 NM_018943.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.26

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 22-18126361-C-T is Benign according to our data. Variant chr22-18126361-C-T is described in ClinVar as [Benign]. Clinvar id is 160173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-18126361-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA8	NM_018943.3	c.383C>T	p.Ala128Val	missense_variant	4/5	ENST00000330423.8
TUBA8	NM_001193414.2	c.185C>T	p.Ala62Val	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA8	ENST00000330423.8	c.383C>T	p.Ala128Val	missense_variant	4/5	1	NM_018943.3	P1
	ENST00000623543.1	n.4794G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00750 AC: 1141 AN: 152184 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00709 AC: 1780 AN: 251010 Hom.: 5 AF XY: 0.00733 AC XY: 995 AN XY: 135800

Gnomad AFR exome AF: 0.00248

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00536

Gnomad FIN exome AF: 0.00439

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.0111 AC: 16251 AN: 1461816 Hom.: 119 Cov.: 31 AF XY: 0.0109 AC XY: 7936 AN XY: 727208

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00616

Gnomad4 FIN exome AF: 0.00470

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.00979

GnomAD4 genome AF: 0.00749 AC: 1140 AN: 152302 Hom.: 9 Cov.: 32 AF XY: 0.00698 AC XY: 520 AN XY: 74470

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.0107 Hom.: 24

Bravo AF: 0.00724

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0113 AC: 97

ExAC AF: 0.00699 AC: 849

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.0125

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ENSG00000280007: BS1, BS2; TUBA8: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 23, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	26
Dann	Benign	0.97
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.68	N;N;N
REVEL	Benign	0.16
Sift4G	Benign	0.091	T;T;T
Polyphen		0.039, 0.22	.;B;B
Vest4		0.47
MVP		0.89
MPC		0.27
ClinPred		0.020	T
GERP RS		5.5
Varity_R		0.12
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2234331; hg19: chr22-18609128; COSMIC: COSV99042944; COSMIC: COSV99042944;