2-219271517-C-T

Variant names:

• chr2-219271517-C-T
• rs3731891
• NM_001355221.1:c.544C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001355221.1(TUBA4B):​c.544C>T​(p.Arg182Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,614,144 control chromosomes in the GnomAD database, including 860 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.041 (254 hom., cov: 32)
  • Exomes 𝑓: 0.017 (606 hom.)
• Consequence: TUBA4B NM_001355221.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

Genes affected

TUBA4B (HGNC:18637): (tubulin alpha 4b) 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. Predicted to be active in cytoplasm and microtubule. [provided by Alliance of Genome Resources, Apr 2022]

TUBA4A (HGNC:12407): (tubulin alpha 4a) Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulin. The genes encoding these microtubule constituents are part of the tubulin superfamily, which is composed of six distinct families. Genes from the alpha, beta and gamma tubulin families are found in all eukaryotes. The alpha and beta tubulins represent the major components of microtubules, while gamma tubulin plays a critical role in the nucleation of microtubule assembly. There are multiple alpha and beta tubulin genes and they are highly conserved among and between species. This gene encodes an alpha tubulin that is a highly conserved homolog of a rat testis-specific alpha tubulin. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068460405).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA4B	NM_001355221.1	c.544C>T	p.Arg182Cys	missense_variant	Exon 4 of 4	ENST00000490341.3	NP_001342150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA4B	ENST00000490341.3	c.544C>T	p.Arg182Cys	missense_variant	Exon 4 of 4	2	NM_001355221.1	ENSP00000487719.1

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6287 AN: 152146 Hom.: 251 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0256 AC: 6434 AN: 251416 Hom.: 232 AF XY: 0.0236 AC XY: 3206 AN XY: 135898

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00862

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.0981

Gnomad SAS exome AF: 0.0122

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0168 AC: 24539 AN: 1461880 Hom.: 606 Cov.: 68 AF XY: 0.0163 AC XY: 11846 AN XY: 727244

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.00941

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.0170

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0225

GnomAD4 genome AF: 0.0414 AC: 6308 AN: 152264 Hom.: 254 Cov.: 32 AF XY: 0.0415 AC XY: 3089 AN XY: 74446

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0168

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0277 Hom.: 21

Bravo AF: 0.0439

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0104 AC: 40

ExAC AF: 0.0278 AC: 3378

Asia WGS AF: 0.0560 AC: 194 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Benign	0.86
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0068	T
PrimateAI	Uncertain	0.68	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
GERP RS		2.7
Varity_R		0.089
gMVP		0.33

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: rs3731891; hg19: chr2-220136239; COSMIC: COSV67524711;