rs140262591

Positions:

• chr12-111470741-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001372574.1(ATXN2):​c.2526A>G​(p.Val842=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,614,008 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (20 hom.)
• Consequence: ATXN2 NM_001372574.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.03910
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.11

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 12-111470741-T-C is Benign according to our data. Variant chr12-111470741-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210509.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}. Variant chr12-111470741-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BS2: High AC in GnomAd4 at 486 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.2526A>G	p.Val842=	splice_region_variant, synonymous_variant	19/25	ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1	c.2526A>G	p.Val842=	splice_region_variant, synonymous_variant	19/25		NM_001372574.1	ENSP00000500925	A2

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 486 AN: 152066 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00280 AC: 704 AN: 251170 Hom.: 3 AF XY: 0.00291 AC XY: 395 AN XY: 135758

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00491

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00445 AC: 6512 AN: 1461824 Hom.: 20 Cov.: 31 AF XY: 0.00437 AC XY: 3180 AN XY: 727214

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00539

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.00319 AC: 486 AN: 152184 Hom.: 1 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74402

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00532

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00458 Hom.: 4

Bravo AF: 0.00335

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ATXN2: BP4, BS1, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 27, 2014

- -

ATXN2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.039
dbscSNV1_RF	Benign	0.16
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: rs140262591; hg19: chr12-111908545;