12-111472415-A-G

Position:

• chr12-111472415-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372574.1(ATXN2):​c.2525-1673T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 151,972 control chromosomes in the GnomAD database, including 36,983 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 0.67 (36983 hom., cov: 31)
• Consequence: ATXN2 NM_001372574.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.206

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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.2525-1673T>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.2525-1673T>C		intron_variant			NM_001372574.1	ENSP00000500925	A2

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101382 AN: 151854 Hom.: 36910 Cov.: 31

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.703

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.612

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.639

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

GnomAD4 genome AF: 0.668 AC: 101519 AN: 151972 Hom.: 36983 Cov.: 31 AF XY: 0.680 AC XY: 50454 AN XY: 74250

Gnomad4 AFR AF: 0.916

Gnomad4 AMR AF: 0.704

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.904

Gnomad4 FIN AF: 0.573

Gnomad4 NFE AF: 0.502

Gnomad4 OTH AF: 0.642

Alfa AF: 0.533 Hom.: 43650

Bravo AF: 0.684

Asia WGS AF: 0.940 AC: 3267 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.3
DANN	Benign	0.51

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: rs10774625; hg19: chr12-111910219;