12-111598978-TTGCTGCTGCTGCTGCTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant names:

• chr12-111598978-T-TTGC
• rs193922927
• NM_001372574.1:c.54_56dupGCA

Variant summary

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

The NM_001372574.1(ATXN2):​c.54_56dupGCA​(p.Gln19dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 137,636 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q19Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN2 NM_001372574.1 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.273

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 152 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.54_56dupGCA	p.Gln19dup	disruptive_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.54_56dupGCA	p.Gln19dup	disruptive_inframe_insertion	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 152 AN: 137564 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00194

Gnomad ASJ AF: 0.000311

Gnomad EAS AF: 0.000230

Gnomad SAS AF: 0.000231

Gnomad FIN AF: 0.000583

Gnomad MID AF: 0.00352

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00107

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00105 AC: 1213 AN: 1154180 Hom.: 0 Cov.: 74 AF XY: 0.00101 AC XY: 574 AN XY: 567646

Gnomad4 AFR exome AF: 0.000482

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.0000453

Gnomad4 EAS exome AF: 0.0000384

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.000841

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00110 AC: 152 AN: 137636 Hom.: 0 Cov.: 32 AF XY: 0.00115 AC XY: 77 AN XY: 66994

Gnomad4 AFR AF: 0.000344

Gnomad4 AMR AF: 0.00194

Gnomad4 ASJ AF: 0.000311

Gnomad4 EAS AF: 0.000230

Gnomad4 SAS AF: 0.000231

Gnomad4 FIN AF: 0.000583

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.00106

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: rs193922927; hg19: chr12-112036782;