12-111457399-C-G

Variant names:

• chr12-111457399-C-G
• rs2301622
• NM_001372574.1:c.2897-40G>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.2897-40G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,564,278 control chromosomes in the GnomAD database, including 74,596 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 (15019 hom., cov: 32)
  • Exomes 𝑓: 0.25 (59577 hom.)
• Consequence: ATXN2 NM_001372574.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0430
• Publications: 20 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 = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.2897-40G>C		intron_variant	Intron 21 of 24	ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1	c.2897-40G>C		intron_variant	Intron 21 of 24		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57572 AN: 151842 Hom.: 14981 Cov.: 32

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.901

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.363

GnomAD2 exomes AF: 0.341 AC: 73489 AN: 215648 AF XY: 0.326

Gnomad AFR exome AF: 0.699

Gnomad AMR exome AF: 0.378

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.921

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.254 AC: 358727 AN: 1412318 Hom.: 59577 Cov.: 31 AF XY: 0.254 AC XY: 177212 AN XY: 698174

African (AFR) AF: 0.700 AC: 22580 AN: 32238

American (AMR) AF: 0.359 AC: 13841 AN: 38554

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 2677 AN: 23154

East Asian (EAS) AF: 0.878 AC: 34284 AN: 39034

South Asian (SAS) AF: 0.360 AC: 28439 AN: 78900

European-Finnish (FIN) AF: 0.192 AC: 9941 AN: 51884

Middle Eastern (MID) AF: 0.395 AC: 2183 AN: 5522

European-Non Finnish (NFE) AF: 0.210 AC: 227689 AN: 1084828

Other (OTH) AF: 0.294 AC: 17093 AN: 58204

GnomAD4 genome AF: 0.380 AC: 57675 AN: 151960 Hom.: 15019 Cov.: 32 AF XY: 0.379 AC XY: 28150 AN XY: 74296

African (AFR) AF: 0.685 AC: 28361 AN: 41380

American (AMR) AF: 0.335 AC: 5118 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 397 AN: 3468

East Asian (EAS) AF: 0.900 AC: 4638 AN: 5152

South Asian (SAS) AF: 0.375 AC: 1808 AN: 4822

European-Finnish (FIN) AF: 0.187 AC: 1976 AN: 10586

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

European-Non Finnish (NFE) AF: 0.211 AC: 14368 AN: 67972

Other (OTH) AF: 0.360 AC: 759 AN: 2108

Alfa AF: 0.260 Hom.: 1296

Bravo AF: 0.410

Asia WGS AF: 0.569 AC: 1979 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.9
DANN	Benign	0.64
PhyloP100		0.043
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: rs2301622; hg19: chr12-111895203;