12-111598978-TTGCTGCTGCTGCTGCTGCTGCTGCTGC-TTGCTGCTGCTGC

Variant names:

• chr12-111598978-TTGCTGCTGCTGCTGC-T
• rs193922927
• NM_001372574.1:c.42_56delGCAGCAGCAGCAGCA

Variant summary

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

The NM_001372574.1(ATXN2):​c.42_56delGCAGCAGCAGCAGCA​(p.Gln15_Gln19del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000897 in 1,292,640 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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. Synonymous variant affecting the same amino acid position (i.e. Q14Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: ATXN2 NM_001372574.1 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93
• Publications: 2 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 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN2	NM_001372574.1	c.42_56delGCAGCAGCAGCAGCA	p.Gln15_Gln19del	disruptive_inframe_deletion	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_56delGCAGCAGCAGCAGCA	p.Gln15_Gln19del	disruptive_inframe_deletion	Exon 1 of 25		NM_001372574.1	ENSP00000500925.1

Frequencies

GnomAD3 genomes AF: 0.0000872 AC: 12 AN: 137574 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000795

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000144

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000900 AC: 104 AN: 1155066 Hom.: 0 AF XY: 0.0000986 AC XY: 56 AN XY: 568074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000402 AC: 1 AN: 24896

American (AMR) AF: 0.0000736 AC: 2 AN: 27170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22080

East Asian (EAS) AF: 0.0000768 AC: 2 AN: 26042

South Asian (SAS) AF: 0.0000507 AC: 3 AN: 59212

European-Finnish (FIN) AF: 0.0000623 AC: 2 AN: 32118

Middle Eastern (MID) AF: 0.000296 AC: 1 AN: 3380

European-Non Finnish (NFE) AF: 0.0000976 AC: 89 AN: 912144

Other (OTH) AF: 0.0000833 AC: 4 AN: 48024

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000872 AC: 12 AN: 137574 Hom.: 0 Cov.: 32 AF XY: 0.000105 AC XY: 7 AN XY: 66906

African (AFR) AF: 0.0000795 AC: 3 AN: 37740

American (AMR) AF: 0.00 AC: 0 AN: 13900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3214

East Asian (EAS) AF: 0.00 AC: 0 AN: 4356

South Asian (SAS) AF: 0.00 AC: 0 AN: 4338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000144 AC: 9 AN: 62456

Other (OTH) AF: 0.00 AC: 0 AN: 1864

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=173/27	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs193922927; hg19: chr12-112036782;