chr12-111556082-A-G

Variant names:

• chr12-111556082-A-G
• rs593226
• NM_001372574.1:c.252-163T>C

Variant summary

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

The NM_001372574.1(ATXN2):​c.252-163T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 152,064 control chromosomes in the GnomAD database, including 19,431 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 0.44 (19431 hom., cov: 31)
• Consequence: ATXN2 NM_001372574.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.121
• Publications: 18 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.918 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.252-163T>C		intron	N/A	NP_001359503.1
	ATXN2	NM_002973.4		c.252-163T>C		intron	N/A	NP_002964.4
	ATXN2	NM_001310121.1		c.-64-163T>C		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.252-163T>C		intron	N/A	ENSP00000500925.1
	ATXN2	ENST00000550104.5	TSL:1	c.732-163T>C		intron	N/A	ENSP00000446576.2
	ATXN2	ENST00000608853.5	TSL:1	c.252-163T>C		intron	N/A	ENSP00000476504.1

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66237 AN: 151946 Hom.: 19375 Cov.: 31

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.415

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

GnomAD4 genome AF: 0.436 AC: 66357 AN: 152064 Hom.: 19431 Cov.: 31 AF XY: 0.439 AC XY: 32660 AN XY: 74354

African (AFR) AF: 0.775 AC: 32119 AN: 41440

American (AMR) AF: 0.395 AC: 6035 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 499 AN: 3464

East Asian (EAS) AF: 0.940 AC: 4873 AN: 5186

South Asian (SAS) AF: 0.594 AC: 2865 AN: 4824

European-Finnish (FIN) AF: 0.207 AC: 2190 AN: 10580

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16576 AN: 67980

Other (OTH) AF: 0.414 AC: 874 AN: 2110

Alfa AF: 0.286 Hom.: 4626

Bravo AF: 0.466

Asia WGS AF: 0.731 AC: 2539 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.8
DANN	Benign	0.51
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: rs593226; hg19: chr12-111993886;