rs695872

Variant names:

• chr12-111599125-G-A
• rs695872
• ENST00000550104.5:c.390C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000550104.5(ATXN2):​c.390C>T​(p.Arg130Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,245,850 control chromosomes in the GnomAD database, including 351,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.61 (31878 hom., cov: 29)
  • Exomes 𝑓: 0.75 (319773 hom.)
• Consequence: ATXN2 ENST00000550104.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -0.132
• Publications: 23 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-AS (HGNC:51838): (ATXN2 antisense RNA)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 12-111599125-G-A is Benign according to our data. Variant chr12-111599125-G-A is described in ClinVar as Benign. ClinVar VariationId is 128508.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.132 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.-91C>T		5_prime_UTR_variant	Exon 1 of 25	ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1	c.-91C>T		5_prime_UTR_variant	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.609 AC: 91398 AN: 150064 Hom.: 31888 Cov.: 29

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.0934

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.823

Gnomad MID AF: 0.619

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.615

GnomAD2 exomes AF: 0.787 AC: 2080 AN: 2644 AF XY: 0.786

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.671

Gnomad ASJ exome AF: 0.919

Gnomad FIN exome AF: 0.845

Gnomad NFE exome AF: 0.810

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.754 AC: 825798 AN: 1095676 Hom.: 319773 Cov.: 69 AF XY: 0.756 AC XY: 395318 AN XY: 522780

African (AFR) AF: 0.296 AC: 6613 AN: 22326

American (AMR) AF: 0.573 AC: 4706 AN: 8208

Ashkenazi Jewish (ASJ) AF: 0.874 AC: 12389 AN: 14176

East Asian (EAS) AF: 0.139 AC: 3541 AN: 25484

South Asian (SAS) AF: 0.671 AC: 16656 AN: 24824

European-Finnish (FIN) AF: 0.815 AC: 17989 AN: 22060

Middle Eastern (MID) AF: 0.643 AC: 1890 AN: 2940

European-Non Finnish (NFE) AF: 0.785 AC: 731568 AN: 931924

Other (OTH) AF: 0.696 AC: 30446 AN: 43734

GnomAD4 genome AF: 0.609 AC: 91402 AN: 150174 Hom.: 31878 Cov.: 29 AF XY: 0.609 AC XY: 44678 AN XY: 73366

African (AFR) AF: 0.309 AC: 12687 AN: 40994

American (AMR) AF: 0.579 AC: 8758 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 3005 AN: 3456

East Asian (EAS) AF: 0.0939 AC: 470 AN: 5006

South Asian (SAS) AF: 0.630 AC: 3008 AN: 4774

European-Finnish (FIN) AF: 0.823 AC: 8422 AN: 10228

Middle Eastern (MID) AF: 0.621 AC: 180 AN: 290

European-Non Finnish (NFE) AF: 0.785 AC: 52812 AN: 67312

Other (OTH) AF: 0.618 AC: 1294 AN: 2094

Alfa AF: 0.685 Hom.: 4673

Bravo AF: 0.571

Asia WGS AF: 0.413 AC: 1382 AN: 3344

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 2 Benign:1

Oct 06, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.93
PhyloP100		-0.13
PromoterAI		-0.030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs695872; hg19: chr12-112036929; COSMIC: COSV108225761; COSMIC: COSV108225761;