2-219253950-CGGGGGG-CGGGGGGG

Variant names:

• chr2-219253950-C-CG
• rs3051654
• NM_001355221.1:c.12+541dupG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001355221.1(TUBA4B):​c.12+541dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 503,686 control chromosomes in the GnomAD database, including 206 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.054 (205 hom., cov: 30)
  • Exomes 𝑓: 0.021 (1 hom.)
• Consequence: TUBA4B NM_001355221.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.431
• Publications: 0 publications found

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]

TUBA4A Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 22

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-219253950-C-CG is Benign according to our data. Variant chr2-219253950-C-CG is described in ClinVar as Benign. ClinVar VariationId is 1235911.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001355221.1. 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
	TUBA4B	NM_001355221.1	MANE Select	c.12+541dupG		intron	N/A	NP_001342150.1	Q9H853
	TUBA4A	NM_001278552.2		c.-43+144dupC		intron	N/A	NP_001265481.1	P68366-2
	TUBA4A	NM_006000.3	MANE Select	c.-93dupC		upstream_gene	N/A	NP_005991.1	P68366-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA4B	ENST00000490341.3	TSL:2 MANE Select	c.12+531_12+532insG		intron	N/A	ENSP00000487719.1	Q9H853
	TUBA4B	ENST00000473885.5	TSL:1	n.177+531_177+532insG		intron	N/A
	TUBA4B	ENST00000485041.5	TSL:1	n.177+531_177+532insG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0538 AC: 6777 AN: 126068 Hom.: 205 Cov.: 30

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0235

Gnomad EAS AF: 0.00933

Gnomad SAS AF: 0.0216

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.0294

Gnomad NFE AF: 0.0467

Gnomad OTH AF: 0.0384

GnomAD4 exome AF: 0.0207 AC: 7817 AN: 377558 Hom.: 1 Cov.: 12 AF XY: 0.0212 AC XY: 3900 AN XY: 184024

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0342 AC: 396 AN: 11584

American (AMR) AF: 0.0308 AC: 163 AN: 5294

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 167 AN: 7328

East Asian (EAS) AF: 0.00378 AC: 66 AN: 17464

South Asian (SAS) AF: 0.0181 AC: 169 AN: 9340

European-Finnish (FIN) AF: 0.0202 AC: 469 AN: 23168

Middle Eastern (MID) AF: 0.0185 AC: 24 AN: 1298

European-Non Finnish (NFE) AF: 0.0209 AC: 5934 AN: 284438

Other (OTH) AF: 0.0243 AC: 429 AN: 17644

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0538 AC: 6781 AN: 126128 Hom.: 205 Cov.: 30 AF XY: 0.0519 AC XY: 3183 AN XY: 61324

African (AFR) AF: 0.0880 AC: 3183 AN: 36176

American (AMR) AF: 0.0331 AC: 420 AN: 12708

Ashkenazi Jewish (ASJ) AF: 0.0235 AC: 68 AN: 2896

East Asian (EAS) AF: 0.00937 AC: 39 AN: 4162

South Asian (SAS) AF: 0.0217 AC: 80 AN: 3686

European-Finnish (FIN) AF: 0.0212 AC: 172 AN: 8114

Middle Eastern (MID) AF: 0.0318 AC: 7 AN: 220

European-Non Finnish (NFE) AF: 0.0467 AC: 2604 AN: 55710

Other (OTH) AF: 0.0380 AC: 65 AN: 1712

Alfa AF: 0.00527 Hom.: 7

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
Mutation Taster		=300/0	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: rs3051654; hg19: chr2-220118672;