12-111457399-C-G

Position:

• chr12-111457399-C-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.2897-40G>C		intron_variant		ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1	c.2897-40G>C		intron_variant			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

GnomAD3 exomes AF: 0.341 AC: 73489 AN: 215648 Hom.: 17814 AF XY: 0.326 AC XY: 37778 AN XY: 115836

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 SAS exome AF: 0.365

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

Gnomad4 AFR exome AF: 0.700

Gnomad4 AMR exome AF: 0.359

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.878

Gnomad4 SAS exome AF: 0.360

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.294

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

Gnomad4 AFR AF: 0.685

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.900

Gnomad4 SAS AF: 0.375

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.360

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2301622; hg19: chr12-111895203;