12-111598844-GCCGAGGACGAGGAGA-GCCGAGGACGAGGAGACCGAGGACGAGGAGA

Variant names:

• chr12-111598844-G-GCCGAGGACGAGGAGA
• rs778119853
• NM_001372574.1:c.176_190dupTCTCCTCGTCCTCGG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001372574.1(ATXN2):​c.176_190dupTCTCCTCGTCCTCGG​(p.Val59_Ser63dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000594 in 1,472,762 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00061 (1 hom.)
• Consequence: ATXN2 NM_001372574.1 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001372574.1
• BS2: High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.176_190dupTCTCCTCGTCCTCGG	p.Val59_Ser63dup	conservative_inframe_insertion	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.176_190dupTCTCCTCGTCCTCGG	p.Val59_Ser63dup	conservative_inframe_insertion	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.000462 AC: 70 AN: 151390 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000919

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000482

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000384

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000173 AC: 14 AN: 81016 AF XY: 0.000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000422

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.000609 AC: 805 AN: 1321264 Hom.: 1 Cov.: 29 AF XY: 0.000601 AC XY: 392 AN XY: 651982

African (AFR) AF: 0.000493 AC: 13 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 27688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23076

East Asian (EAS) AF: 0.00 AC: 0 AN: 28608

South Asian (SAS) AF: 0.0000135 AC: 1 AN: 73890

European-Finnish (FIN) AF: 0.000703 AC: 23 AN: 32698

Middle Eastern (MID) AF: 0.000258 AC: 1 AN: 3876

European-Non Finnish (NFE) AF: 0.000684 AC: 718 AN: 1050414

Other (OTH) AF: 0.000897 AC: 49 AN: 54620

GnomAD4 genome AF: 0.000462 AC: 70 AN: 151498 Hom.: 0 Cov.: 31 AF XY: 0.000405 AC XY: 30 AN XY: 74044

African (AFR) AF: 0.000916 AC: 38 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000482 AC: 5 AN: 10378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000384 AC: 26 AN: 67716

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.0000470 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=76/24	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs778119853; hg19: chr12-112036648;