chr12-111536476-T-G

Variant names:

• chr12-111536476-T-G
• rs616668
• NM_001372574.1:c.572-11160A>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.572-11160A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 151,896 control chromosomes in the GnomAD database, including 3,230 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 0.20 (3230 hom., cov: 31)
• Consequence: ATXN2 NM_001372574.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.572-11160A>C		intron_variant	Intron 5 of 24	ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1	c.572-11160A>C		intron_variant	Intron 5 of 24		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30816 AN: 151778 Hom.: 3229 Cov.: 31

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.203 AC: 30826 AN: 151896 Hom.: 3230 Cov.: 31 AF XY: 0.201 AC XY: 14906 AN XY: 74256

African (AFR) AF: 0.210 AC: 8695 AN: 41452

American (AMR) AF: 0.175 AC: 2668 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3464

East Asian (EAS) AF: 0.324 AC: 1672 AN: 5156

South Asian (SAS) AF: 0.261 AC: 1256 AN: 4812

European-Finnish (FIN) AF: 0.173 AC: 1819 AN: 10526

Middle Eastern (MID) AF: 0.305 AC: 89 AN: 292

European-Non Finnish (NFE) AF: 0.201 AC: 13655 AN: 67936

Other (OTH) AF: 0.218 AC: 460 AN: 2106

Alfa AF: 0.184 Hom.: 1408

Bravo AF: 0.205

Asia WGS AF: 0.298 AC: 1035 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.53
PhyloP100		0.28
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: rs616668; hg19: chr12-111974280;