rs140262591

Variant names:

• chr12-111470741-T-C
• rs140262591
• NM_001372574.1:c.2526A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001372574.1(ATXN2):​c.2526A>G​(p.Val842Val) 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
• Publications: 7 publications found

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]

ATXN2 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.054).
• 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 VariationId is 210509.
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BS2: High AC in GnomAd4 at 486 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372574.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	NM_001372574.1	MANE Select	c.2526A>G	p.Val842Val	splice_region synonymous	Exon 19 of 25	NP_001359503.1	A0A5F9ZI57
	ATXN2	NM_002973.4		c.2520A>G	p.Val840Val	splice_region synonymous	Exon 19 of 25	NP_002964.4	V9GY86
	ATXN2	NM_001310121.1		c.2205A>G	p.Val735Val	splice_region synonymous	Exon 19 of 26	NP_001297050.1	Q2M2R5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	ENST00000673436.1	MANE Select	c.2526A>G	p.Val842Val	splice_region synonymous	Exon 19 of 25	ENSP00000500925.1	A0A5F9ZI57
	ATXN2	ENST00000550104.5	TSL:1	c.3000A>G	p.Val1000Val	splice_region synonymous	Exon 19 of 25	ENSP00000446576.2	Q99700-1
	ATXN2	ENST00000608853.5	TSL:1	c.2520A>G	p.Val840Val	splice_region synonymous	Exon 19 of 25	ENSP00000476504.1	V9GY86

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

GnomAD2 exomes AF: 0.00280 AC: 704 AN: 251170 AF XY: 0.00291

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 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

African (AFR) AF: 0.000687 AC: 23 AN: 33476

American (AMR) AF: 0.00157 AC: 70 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00172 AC: 148 AN: 86254

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53410

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.00539 AC: 5993 AN: 1111976

Other (OTH) AF: 0.00351 AC: 212 AN: 60396

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

African (AFR) AF: 0.00106 AC: 44 AN: 41510

American (AMR) AF: 0.00216 AC: 33 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00532 AC: 362 AN: 68008

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00437 Hom.: 4

Bravo AF: 0.00335

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	ATXN2-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Uncertain	0.99
PhyloP100		1.1
PromoterAI		-0.030	Neutral
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs140262591; hg19: chr12-111908545;