12-111565579-G-T

Variant names:

• chr12-111565579-G-T
• rs616513
• NM_001372574.1:c.252-9660C>A

Variant summary

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

The NM_001372574.1(ATXN2):​c.252-9660C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 151,944 control chromosomes in the GnomAD database, including 14,919 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 0.38 (14919 hom., cov: 32)
• Consequence: ATXN2 NM_001372574.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.730
• Publications: 12 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 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.252-9660C>A		intron	N/A	NP_001359503.1
	ATXN2	NM_002973.4		c.252-9660C>A		intron	N/A	NP_002964.4
	ATXN2	NM_001310121.1		c.-64-9660C>A		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.252-9660C>A		intron	N/A	ENSP00000500925.1
	ATXN2	ENST00000550104.5	TSL:1	c.732-9660C>A		intron	N/A	ENSP00000446576.2
	ATXN2	ENST00000608853.5	TSL:1	c.252-9660C>A		intron	N/A	ENSP00000476504.1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57029 AN: 151826 Hom.: 14881 Cov.: 32

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.361

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

GnomAD4 genome AF: 0.376 AC: 57131 AN: 151944 Hom.: 14919 Cov.: 32 AF XY: 0.375 AC XY: 27852 AN XY: 74270

African (AFR) AF: 0.685 AC: 28402 AN: 41446

American (AMR) AF: 0.331 AC: 5045 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 398 AN: 3468

East Asian (EAS) AF: 0.900 AC: 4671 AN: 5190

South Asian (SAS) AF: 0.367 AC: 1759 AN: 4798

European-Finnish (FIN) AF: 0.175 AC: 1845 AN: 10538

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14013 AN: 67948

Other (OTH) AF: 0.358 AC: 753 AN: 2104

Alfa AF: 0.250 Hom.: 7482

Bravo AF: 0.407

Asia WGS AF: 0.568 AC: 1975 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.6
DANN	Benign	0.72
PhyloP100		-0.73
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: rs616513; hg19: chr12-112003383;