12-111466567-T-A

Variant names:

• chr12-111466567-T-A
• rs4766578
• NM_001372574.1:c.2843-1852A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372574.1(ATXN2):​c.2843-1852A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 152,184 control chromosomes in the GnomAD database, including 37,051 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.67 (37051 hom., cov: 33)
• Consequence: ATXN2 NM_001372574.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.121
• Publications: 110 publications found

Genes affected

ATXN2 (HGNC:10555): (ataxin 2) This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ATXN2 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372574.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	NM_001372574.1	MANE Select	c.2843-1852A>T		intron	N/A	NP_001359503.1
	ATXN2	NM_002973.4		c.2837-1852A>T		intron	N/A	NP_002964.4
	ATXN2	NM_001310121.1		c.2522-1852A>T		intron	N/A	NP_001297050.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	ENST00000673436.1	MANE Select	c.2843-1852A>T		intron	N/A	ENSP00000500925.1
	ATXN2	ENST00000550104.5	TSL:1	c.3317-1852A>T		intron	N/A	ENSP00000446576.2
	ATXN2	ENST00000608853.5	TSL:1	c.2837-1852A>T		intron	N/A	ENSP00000476504.1

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101562 AN: 152066 Hom.: 36978 Cov.: 33

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.703

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.903

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.640

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.668 AC: 101699 AN: 152184 Hom.: 37051 Cov.: 33 AF XY: 0.680 AC XY: 50546 AN XY: 74380

African (AFR) AF: 0.916 AC: 38086 AN: 41570

American (AMR) AF: 0.703 AC: 10754 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1144 AN: 3468

East Asian (EAS) AF: 0.998 AC: 5180 AN: 5190

South Asian (SAS) AF: 0.903 AC: 4355 AN: 4824

European-Finnish (FIN) AF: 0.573 AC: 6052 AN: 10562

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34100 AN: 67966

Other (OTH) AF: 0.643 AC: 1354 AN: 2106

Alfa AF: 0.542 Hom.: 13271

Bravo AF: 0.684

Asia WGS AF: 0.940 AC: 3267 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.75
PhyloP100		0.12
Mutation Taster		=100/0	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: rs4766578; hg19: chr12-111904371;