2-219254060-T-G

Variant names:

• chr2-219254060-T-G
• rs2071385
• NM_001355221.1:c.12+641T>G

Variant summary

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

The NM_001355221.1(TUBA4B):​c.12+641T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 476,568 control chromosomes in the GnomAD database, including 5,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2887 hom., cov: 32)
  • Exomes 𝑓: 0.11 (2676 hom.)
• Consequence: TUBA4B NM_001355221.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.218
• Publications: 3 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, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-219254060-T-G is Benign according to our data. Variant chr2-219254060-T-G is described in ClinVar as Benign. ClinVar VariationId is 1260536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 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+641T>G		intron	N/A	NP_001342150.1	Q9H853
	TUBA4A	NM_001278552.2		c.-43+35A>C		intron	N/A	NP_001265481.1	P68366-2
	TUBA4A	NM_006000.3	MANE Select	c.-202A>C		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+641T>G		intron	N/A	ENSP00000487719.1	Q9H853
	TUBA4B	ENST00000473885.5	TSL:1	n.177+641T>G		intron	N/A
	TUBA4B	ENST00000485041.5	TSL:1	n.177+641T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25173 AN: 151950 Hom.: 2875 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0964

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.115 AC: 37182 AN: 324500 Hom.: 2676 Cov.: 4 AF XY: 0.117 AC XY: 19463 AN XY: 166992

African (AFR) AF: 0.320 AC: 2423 AN: 7576

American (AMR) AF: 0.126 AC: 1251 AN: 9908

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 1473 AN: 10136

East Asian (EAS) AF: 0.151 AC: 3497 AN: 23094

South Asian (SAS) AF: 0.204 AC: 3436 AN: 16806

European-Finnish (FIN) AF: 0.0490 AC: 1804 AN: 36832

Middle Eastern (MID) AF: 0.203 AC: 298 AN: 1466

European-Non Finnish (NFE) AF: 0.101 AC: 20229 AN: 199584

Other (OTH) AF: 0.145 AC: 2771 AN: 19098

GnomAD4 genome AF: 0.166 AC: 25210 AN: 152068 Hom.: 2887 Cov.: 32 AF XY: 0.163 AC XY: 12150 AN XY: 74346

African (AFR) AF: 0.322 AC: 13366 AN: 41474

American (AMR) AF: 0.135 AC: 2067 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3460

East Asian (EAS) AF: 0.154 AC: 792 AN: 5138

South Asian (SAS) AF: 0.198 AC: 954 AN: 4820

European-Finnish (FIN) AF: 0.0465 AC: 493 AN: 10608

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0964 AC: 6548 AN: 67956

Other (OTH) AF: 0.178 AC: 375 AN: 2106

Alfa AF: 0.103 Hom.: 410

Bravo AF: 0.180

Asia WGS AF: 0.165 AC: 574 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.4
DANN	Benign	0.54
PhyloP100		-0.22
PromoterAI		-0.038	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2071385; hg19: chr2-220118782; COSMIC: COSV50281813; COSMIC: COSV50281813;