12-111457405-A-C

Variant names:

• chr12-111457405-A-C
• rs12301585
• NM_001372574.1:c.2897-46T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372574.1(ATXN2):​c.2897-46T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,554,002 control chromosomes in the GnomAD database, including 5,021 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (2673 hom., cov: 32)
  • Exomes 𝑓: 0.011 (2348 hom.)
• Consequence: ATXN2 NM_001372574.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.213
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.351 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.2897-46T>G		intron	N/A	NP_001359503.1
	ATXN2	NM_002973.4		c.2891-46T>G		intron	N/A	NP_002964.4
	ATXN2	NM_001310121.1		c.2576-46T>G		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.2897-46T>G		intron	N/A	ENSP00000500925.1
	ATXN2	ENST00000550104.5	TSL:1	c.3371-46T>G		intron	N/A	ENSP00000446576.2
	ATXN2	ENST00000608853.5	TSL:1	c.2891-46T>G		intron	N/A	ENSP00000476504.1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15574 AN: 151864 Hom.: 2653 Cov.: 32

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.0662

GnomAD2 exomes AF: 0.0313 AC: 6566 AN: 209634 AF XY: 0.0234

Gnomad AFR exome AF: 0.361

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.00303

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.0111 AC: 15616 AN: 1402020 Hom.: 2348 Cov.: 29 AF XY: 0.00996 AC XY: 6896 AN XY: 692224

African (AFR) AF: 0.371 AC: 11860 AN: 31932

American (AMR) AF: 0.0238 AC: 892 AN: 37414

Ashkenazi Jewish (ASJ) AF: 0.00342 AC: 77 AN: 22520

East Asian (EAS) AF: 0.00 AC: 0 AN: 38890

South Asian (SAS) AF: 0.00363 AC: 279 AN: 76922

European-Finnish (FIN) AF: 0.0000389 AC: 2 AN: 51444

Middle Eastern (MID) AF: 0.0262 AC: 143 AN: 5464

European-Non Finnish (NFE) AF: 0.000928 AC: 1002 AN: 1079714

Other (OTH) AF: 0.0236 AC: 1361 AN: 57720

GnomAD4 genome AF: 0.103 AC: 15642 AN: 151982 Hom.: 2673 Cov.: 32 AF XY: 0.0988 AC XY: 7341 AN XY: 74310

African (AFR) AF: 0.356 AC: 14712 AN: 41366

American (AMR) AF: 0.0418 AC: 638 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00169 AC: 115 AN: 67976

Other (OTH) AF: 0.0665 AC: 140 AN: 2106

Alfa AF: 0.0442 Hom.: 357

Bravo AF: 0.118

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.40
PhyloP100		0.21
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: rs12301585; hg19: chr12-111895209;