12-111598976-TGTTGCTGCTGCTGCTGC-T

Variant names:

• chr12-111598976-TGTTGCTGCTGCTGCTGC-T
• rs759304594
• NM_001372574.1:c.42_58delGCAGCAGCAGCAGCAAC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001372574.1(ATXN2):​c.42_58delGCAGCAGCAGCAGCAAC​(p.Gln15AlafsTer69) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,429,448 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars). Synonymous variant affecting the same amino acid position (i.e. Q14Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: ATXN2 NM_001372574.1 frameshift
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.93

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 12-111598976-TGTTGCTGCTGCTGCTGC-T is Benign according to our data. Variant chr12-111598976-TGTTGCTGCTGCTGCTGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 3043122.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 540 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.42_58delGCAGCAGCAGCAGCAAC	p.Gln15AlafsTer69	frameshift_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.42_58delGCAGCAGCAGCAGCAAC	p.Gln15AlafsTer69	frameshift_variant	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 538 AN: 147044 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00323

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.000991

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.00488

GnomAD4 exome AF: 0.00239 AC: 3069 AN: 1282330 Hom.: 6 AF XY: 0.00238 AC XY: 1510 AN XY: 633398

Gnomad4 AFR exome AF: 0.00456

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000418

Gnomad4 EAS exome AF: 0.00647

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.00143

Gnomad4 NFE exome AF: 0.00240

Gnomad4 OTH exome AF: 0.00228

GnomAD4 genome AF: 0.00367 AC: 540 AN: 147118 Hom.: 1 Cov.: 30 AF XY: 0.00350 AC XY: 252 AN XY: 71928

Gnomad4 AFR AF: 0.00532

Gnomad4 AMR AF: 0.00289

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00324

Gnomad4 SAS AF: 0.00106

Gnomad4 FIN AF: 0.000991

Gnomad4 NFE AF: 0.00367

Gnomad4 OTH AF: 0.00483

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ATXN2-related disorder Benign:1

May 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759304594; hg19: chr12-112036780;