2-130194181-G-T

Variant names:

• chr2-130194181-G-T
• rs13000249
• NM_207312.3:c.661C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207312.3(TUBA3E):​c.661C>A​(p.Arg221Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,603,746 control chromosomes in the GnomAD database, including 74,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (7616 hom., cov: 31)
  • Exomes 𝑓: 0.36 (66426 hom.)
• Consequence: TUBA3E NM_207312.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.19
• Publications: 17 publications found

Genes affected

TUBA3E (HGNC:20765): (tubulin alpha 3e) 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. This gene encodes an alpha tubulin that highly conserved among species. A missense mutation in this gene has been potentially linked to microlissencephaly and global developmental delay. [provided by RefSeq, Jul 2016]

MZT2B (HGNC:25886): (mitotic spindle organizing protein 2B) Located in cytosol; microtubule cytoskeleton; and nucleoplasm. Part of gamma-tubulin large complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032126904).
• BP6: Variant 2-130194181-G-T is Benign according to our data. Variant chr2-130194181-G-T is described in ClinVar as Benign. ClinVar VariationId is 767822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207312.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA3E	NM_207312.3	MANE Select	c.661C>A	p.Arg221Ser	missense	Exon 4 of 5	NP_997195.2	Q6PEY2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA3E	ENST00000312988.9	TSL:1 MANE Select	c.661C>A	p.Arg221Ser	missense	Exon 4 of 5	ENSP00000318197.7	Q6PEY2

Frequencies

GnomAD3 genomes AF: 0.342 AC: 50937 AN: 149150 Hom.: 7613 Cov.: 31

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.351 AC: 86868 AN: 247366 AF XY: 0.352

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.372

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.361

Gnomad OTH exome AF: 0.359

GnomAD4 exome AF: 0.359 AC: 522823 AN: 1454484 Hom.: 66426 Cov.: 129 AF XY: 0.359 AC XY: 260064 AN XY: 723444

African (AFR) AF: 0.224 AC: 7395 AN: 33064

American (AMR) AF: 0.395 AC: 17410 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7578 AN: 25760

East Asian (EAS) AF: 0.374 AC: 14816 AN: 39610

South Asian (SAS) AF: 0.375 AC: 32119 AN: 85730

European-Finnish (FIN) AF: 0.371 AC: 19655 AN: 53030

Middle Eastern (MID) AF: 0.298 AC: 1557 AN: 5232

European-Non Finnish (NFE) AF: 0.362 AC: 401035 AN: 1107898

Other (OTH) AF: 0.354 AC: 21258 AN: 60070

GnomAD4 genome AF: 0.341 AC: 50946 AN: 149262 Hom.: 7616 Cov.: 31 AF XY: 0.343 AC XY: 24933 AN XY: 72772

African (AFR) AF: 0.233 AC: 9445 AN: 40616

American (AMR) AF: 0.428 AC: 6347 AN: 14820

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1038 AN: 3414

East Asian (EAS) AF: 0.424 AC: 2119 AN: 4992

South Asian (SAS) AF: 0.389 AC: 1830 AN: 4706

European-Finnish (FIN) AF: 0.363 AC: 3739 AN: 10300

Middle Eastern (MID) AF: 0.262 AC: 76 AN: 290

European-Non Finnish (NFE) AF: 0.379 AC: 25482 AN: 67172

Other (OTH) AF: 0.327 AC: 670 AN: 2050

Alfa AF: 0.349 Hom.: 1265

ExAC AF: 0.345 AC: 41871

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Benign	0.75
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.031
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.37
Sift4G	Benign	0.079	T
Polyphen		0.61	P
Vest4		0.20
ClinPred		0.098	T
GERP RS		2.0
Varity_R		0.82
gMVP		0.39
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13000249; hg19: chr2-130951754; COSMIC: COSV56058226; COSMIC: COSV56058226;