NM_001372574.1:c.3043-12G>A

Variant names:

• chr12-111456268-C-T
• rs2073950
• NM_001372574.1:c.3043-12G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001372574.1(ATXN2):​c.3043-12G>A variant causes a 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (3228 hom., cov: 33)
  • Exomes 𝑓: 0.21 (32889 hom.)
• Consequence: ATXN2 NM_001372574.1 intron
• Scores: Splicing: ADA: 0.00002213
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -1.76
• Publications: 22 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 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 Benign. ClinVar VariationId is 522365.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	NM_001372574.1	MANE Select	c.3043-12G>A		intron	N/A	NP_001359503.1
	ATXN2	NM_002973.4		c.3037-12G>A		intron	N/A	NP_002964.4
	ATXN2	NM_001310121.1		c.2722-12G>A		intron	N/A	NP_001297050.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	ENST00000673436.1	MANE Select	c.3043-12G>A		intron	N/A	ENSP00000500925.1
	ATXN2	ENST00000550104.5	TSL:1	c.3517-12G>A		intron	N/A	ENSP00000446576.2
	ATXN2	ENST00000608853.5	TSL:1	c.3037-12G>A		intron	N/A	ENSP00000476504.1

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

GnomAD2 exomes AF: 0.210 AC: 52837 AN: 251260 AF XY: 0.213

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 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

African (AFR) AF: 0.189 AC: 6321 AN: 33470

American (AMR) AF: 0.164 AC: 7316 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2859 AN: 26134

East Asian (EAS) AF: 0.279 AC: 11075 AN: 39692

South Asian (SAS) AF: 0.273 AC: 23576 AN: 86248

European-Finnish (FIN) AF: 0.189 AC: 10080 AN: 53406

Middle Eastern (MID) AF: 0.327 AC: 1883 AN: 5764

European-Non Finnish (NFE) AF: 0.206 AC: 229474 AN: 1111626

Other (OTH) AF: 0.216 AC: 13028 AN: 60384

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

African (AFR) AF: 0.194 AC: 8047 AN: 41460

American (AMR) AF: 0.177 AC: 2704 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3470

East Asian (EAS) AF: 0.331 AC: 1712 AN: 5176

South Asian (SAS) AF: 0.267 AC: 1287 AN: 4822

European-Finnish (FIN) AF: 0.185 AC: 1957 AN: 10582

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14008 AN: 67978

Other (OTH) AF: 0.213 AC: 450 AN: 2110

Alfa AF: 0.204 Hom.: 9438

Bravo AF: 0.202

Asia WGS AF: 0.299 AC: 1041 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Spinocerebellar ataxia type 2 Benign:1

Oct 05, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.55
DANN	Benign	0.64
PhyloP100		-1.8
PromoterAI		-0.0090	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2073950; hg19: chr12-111894072; COSMIC: COSV57983646; COSMIC: COSV57983646;