rs1555246688

Variant names:

• chr12-111598963-C-CTGCTGCTGCTGT
• rs1555246688
• NM_001372574.1:c.71_72insACAGCAGCAGCA

Your query was ambiguous. Multiple possible variants found:

• chr12-111598963-C-CTGCTGCTGCTGT
• chr12-111598963-C-CTGCTGCTGCTGTTGCTGCTGCTGCTGT

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_001372574.1(ATXN2):​c.71_72insACAGCAGCAGCA​(p.Gln21_Gln24dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 148,664 control chromosomes in the GnomAD database, including 14 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (60 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN2 NM_001372574.1 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.421
• 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: Benign. The variant received -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001372574.1
• BP6: Variant 12-111598963-C-CTGCTGCTGCTGT is Benign according to our data. Variant chr12-111598963-C-CTGCTGCTGCTGT is described in ClinVar as Benign. ClinVar VariationId is 2643323.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 1718 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372574.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	NM_001372574.1	MANE Select	c.71_72insACAGCAGCAGCA	p.Gln21_Gln24dup	disruptive_inframe_insertion	Exon 1 of 25	NP_001359503.1	A0A5F9ZI57
	ATXN2	NM_002973.4		c.71_72insACAGCAGCAGCA	p.Gln21_Gln24dup	disruptive_inframe_insertion	Exon 1 of 25	NP_002964.4	V9GY86
	ATXN2	NM_001310121.1		c.-65+611_-65+612insACAGCAGCAGCA		intron	N/A	NP_001297050.1	Q2M2R5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN2	ENST00000673436.1	MANE Select	c.71_72insACAGCAGCAGCA	p.Gln21_Gln24dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000500925.1	A0A5F9ZI57
	ATXN2	ENST00000550104.5	TSL:1	c.551_552insACAGCAGCAGCA	p.Gln181_Gln184dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000446576.2	Q99700-1
	ATXN2	ENST00000608853.5	TSL:1	c.71_72insACAGCAGCAGCA	p.Gln21_Gln24dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000476504.1	V9GY86

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1717 AN: 148558 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.00221

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00550

Gnomad EAS AF: 0.000604

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.00884

GnomAD2 exomes AF: 0.00604 AC: 673 AN: 111432 AF XY: 0.00536

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.00700

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.00741

Gnomad OTH exome AF: 0.00671

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00777 AC: 10433 AN: 1342940 Hom.: 60 Cov.: 88 AF XY: 0.00761 AC XY: 5045 AN XY: 662678

African (AFR) AF: 0.00243 AC: 69 AN: 28396

American (AMR) AF: 0.00834 AC: 274 AN: 32844

Ashkenazi Jewish (ASJ) AF: 0.00423 AC: 103 AN: 24334

East Asian (EAS) AF: 0.000763 AC: 25 AN: 32750

South Asian (SAS) AF: 0.00340 AC: 258 AN: 75924

European-Finnish (FIN) AF: 0.0233 AC: 861 AN: 36932

Middle Eastern (MID) AF: 0.00465 AC: 19 AN: 4084

European-Non Finnish (NFE) AF: 0.00800 AC: 8408 AN: 1051610

Other (OTH) AF: 0.00742 AC: 416 AN: 56066

GnomAD4 genome AF: 0.0116 AC: 1718 AN: 148664 Hom.: 14 Cov.: 32 AF XY: 0.0119 AC XY: 862 AN XY: 72718

African (AFR) AF: 0.00571 AC: 229 AN: 40136

American (AMR) AF: 0.0100 AC: 150 AN: 14964

Ashkenazi Jewish (ASJ) AF: 0.00550 AC: 19 AN: 3454

East Asian (EAS) AF: 0.000807 AC: 4 AN: 4954

South Asian (SAS) AF: 0.00230 AC: 11 AN: 4778

European-Finnish (FIN) AF: 0.0245 AC: 252 AN: 10278

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0154 AC: 1032 AN: 66846

Other (OTH) AF: 0.00875 AC: 18 AN: 2058

Alfa AF: 0.00565 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=85/15	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1555246688; hg19: chr12-112036767;