12-111598844-GCCGAGGACGAGGAGA-GCCGAGGACGAGGAGACCGAGGACGAGGAGA

Position:

• chr12-111598844-GCCGAGGACGAGGAGA-GCCGAGGACGAGGAGACCGAGGACGAGGAGA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001372574.1(ATXN2):​c.190_191insTCTCCTCGTCCTCGG​(p.Val59_Ser63dup) variant causes a 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. 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 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73

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.

• 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/exons	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.190_191insTCTCCTCGTCCTCGG	p.Val59_Ser63dup	inframe_insertion	1/25	ENST00000673436.1	NP_001359503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN2	ENST00000673436.1	c.190_191insTCTCCTCGTCCTCGG	p.Val59_Ser63dup	inframe_insertion	1/25		NM_001372574.1	ENSP00000500925	A2

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

GnomAD3 exomes AF: 0.000173 AC: 14 AN: 81016 Hom.: 0 AF XY: 0.000151 AC XY: 7 AN XY: 46314

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 SAS exome AF: 0.0000568

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

Gnomad4 AFR exome AF: 0.000493

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000135

Gnomad4 FIN exome AF: 0.000703

Gnomad4 NFE exome AF: 0.000684

Gnomad4 OTH exome AF: 0.000897

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

Gnomad4 AFR AF: 0.000916

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000482

Gnomad4 NFE AF: 0.000384

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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: rs778119853; hg19: chr12-112036648;