chr12-111569952-C-T

Variant names:

• chr12-111569952-C-T
• rs653178
• NM_001372574.1:c.252-14033G>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.252-14033G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 152,086 control chromosomes in the GnomAD database, including 37,625 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 0.68 (37625 hom., cov: 32)
• Consequence: ATXN2 NM_001372574.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.11
• Publications: 315 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=-0.99).
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	NM_001372574.1	MANE Select	c.252-14033G>A		intron	N/A	NP_001359503.1
	ATXN2	NM_002973.4		c.252-14033G>A		intron	N/A	NP_002964.4
	ATXN2	NM_001310121.1		c.-64-14033G>A		intron	N/A	NP_001297050.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	ENST00000673436.1	MANE Select	c.252-14033G>A		intron	N/A	ENSP00000500925.1
	ATXN2	ENST00000550104.5	TSL:1	c.732-14033G>A		intron	N/A	ENSP00000446576.2
	ATXN2	ENST00000608853.5	TSL:1	c.252-14033G>A		intron	N/A	ENSP00000476504.1

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102532 AN: 151968 Hom.: 37550 Cov.: 32

Gnomad AFR AF: 0.918

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.906

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.631

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.647

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

GnomAD4 genome AF: 0.675 AC: 102671 AN: 152086 Hom.: 37625 Cov.: 32 AF XY: 0.687 AC XY: 51069 AN XY: 74344

African (AFR) AF: 0.918 AC: 38104 AN: 41514

American (AMR) AF: 0.707 AC: 10784 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1143 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5172 AN: 5182

South Asian (SAS) AF: 0.906 AC: 4373 AN: 4826

European-Finnish (FIN) AF: 0.593 AC: 6260 AN: 10564

Middle Eastern (MID) AF: 0.630 AC: 184 AN: 292

European-Non Finnish (NFE) AF: 0.512 AC: 34787 AN: 67958

Other (OTH) AF: 0.651 AC: 1374 AN: 2112

Alfa AF: 0.565 Hom.: 93439

Bravo AF: 0.689

Asia WGS AF: 0.943 AC: 3279 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.10
DANN	Benign	0.33
PhyloP100		-2.1
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: rs653178; hg19: chr12-112007756;