rs2073950

chr12-111456268-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001372574.1(ATXN2):c.3043-12G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,613,538 control chromosomes in the GnomAD database, including 36,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.20 (3228 hom., cov: 33)
  • Exomes 𝑓: 0.21 (32889 hom.)
• Consequence: ATXN2 NM_001372574.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002213
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: -1.76

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-111456268-C-T is Benign according to our data. Variant chr12-111456268-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 522365.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-111456268-C-T is described in Lovd as [Benign]. Variant chr12-111456268-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN2	NM_001372574.1	c.3043-12G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000673436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN2	ENST00000673436.1	c.3043-12G>A		splice_polypyrimidine_tract_variant, intron_variant			NM_001372574.1	A2

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30760 AN: 151972 Hom.: 3227 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.215

GnomAD3 exomes AF: 0.210 AC: 52837 AN: 251260 Hom.: 6056 AF XY: 0.213 AC XY: 28938 AN XY: 135806

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.320

Gnomad SAS exome AF: 0.270

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.209 AC: 305612 AN: 1461446 Hom.: 32889 Cov.: 32 AF XY: 0.210 AC XY: 152638 AN XY: 726990

Gnomad4 AFR exome AF: 0.189

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.279

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.202 AC: 30771 AN: 152092 Hom.: 3228 Cov.: 33 AF XY: 0.201 AC XY: 14950 AN XY: 74362

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.331

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.213

Alfa AF: 0.205 Hom.: 5996

Bravo AF: 0.202

Asia WGS AF: 0.299 AC: 1041 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Spinocerebellar ataxia type 2 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Oct 05, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.55
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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: rs2073950; hg19: chr12-111894072; COSMIC: COSV57983646; COSMIC: COSV57983646;