12-111457405-A-C

Position:

• chr12-111457405-A-C

Variant summary

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

The NM_001372574.1(ATXN2):​c.2897-46T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,554,002 control chromosomes in the GnomAD database, including 5,021 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 0.10 (2673 hom., cov: 32)
  • Exomes 𝑓: 0.011 (2348 hom.)
• Consequence: ATXN2 NM_001372574.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.213

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.2897-46T>G		intron_variant		ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1	c.2897-46T>G		intron_variant			NM_001372574.1	ENSP00000500925	A2

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15574 AN: 151864 Hom.: 2653 Cov.: 32

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.0662

GnomAD3 exomes AF: 0.0313 AC: 6566 AN: 209634 Hom.: 1016 AF XY: 0.0234 AC XY: 2628 AN XY: 112192

Gnomad AFR exome AF: 0.361

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.00303

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00399

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.0111 AC: 15616 AN: 1402020 Hom.: 2348 Cov.: 29 AF XY: 0.00996 AC XY: 6896 AN XY: 692224

Gnomad4 AFR exome AF: 0.371

Gnomad4 AMR exome AF: 0.0238

Gnomad4 ASJ exome AF: 0.00342

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00363

Gnomad4 FIN exome AF: 0.0000389

Gnomad4 NFE exome AF: 0.000928

Gnomad4 OTH exome AF: 0.0236

GnomAD4 genome AF: 0.103 AC: 15642 AN: 151982 Hom.: 2673 Cov.: 32 AF XY: 0.0988 AC XY: 7341 AN XY: 74310

Gnomad4 AFR AF: 0.356

Gnomad4 AMR AF: 0.0418

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.0665

Alfa AF: 0.0471 Hom.: 225

Bravo AF: 0.118

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.40

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: rs12301585; hg19: chr12-111895209;