6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001128164.2(ATXN1):c.624_626del(p.Gln208del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.045 in 1,435,482 control chromosomes in the GnomAD database, including 3,277 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.069 (522 hom., cov: 20)
  • Exomes 𝑓: 0.042 (2755 hom.)
• Consequence: ATXN1 NM_001128164.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.123

Genes affected

ATXN1 (HGNC:10548): (ataxin 1) The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the `pure' cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. The function of the ataxins is not known. This locus has been mapped to chromosome 6, and it has been determined that the diseased allele contains 40-83 CAG repeats, compared to 6-39 in the normal allele, and is associated with spinocerebellar ataxia type 1 (SCA1). Alternative splicing results in multiple transcript variants, with one variant encoding multiple distinct proteins, ATXN1 and Alt-ATXN1, due to the use of overlapping alternate reading frames. [provided by RefSeq, Nov 2017]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 6-16327684-ATGC-A is Benign according to our data. Variant chr6-16327684-ATGC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210503.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr6-16327684-ATGC-A is described in Lovd as [Likely_benign]. Variant chr6-16327684-ATGC-A is described in Lovd as [Benign]. Variant chr6-16327684-ATGC-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.624_626del	p.Gln208del	inframe_deletion	7/8	ENST00000436367.6
ATXN1	NM_000332.4	c.624_626del	p.Gln208del	inframe_deletion	8/9
ATXN1	NM_001357857.2	c.*37_*39del		3_prime_UTR_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.624_626del	p.Gln208del	inframe_deletion	7/8	1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.624_626del	p.Gln208del	inframe_deletion	8/9	1		P1
ATXN1	ENST00000642969.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 9320 AN: 134190 Hom.: 522 Cov.: 20

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0327

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.0848

Gnomad MID AF: 0.0471

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0633

GnomAD4 exome AF: 0.0424 AC: 55235 AN: 1301194 Hom.: 2755 AF XY: 0.0441 AC XY: 28510 AN XY: 646604

Gnomad4 AFR exome AF: 0.0367

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.344

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.0672

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0548

GnomAD4 genome AF: 0.0694 AC: 9315 AN: 134288 Hom.: 522 Cov.: 20 AF XY: 0.0744 AC XY: 4853 AN XY: 65272

Gnomad4 AFR AF: 0.0558

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.0327

Gnomad4 EAS AF: 0.372

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.0848

Gnomad4 NFE AF: 0.0397

Gnomad4 OTH AF: 0.0626

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 27, 2014

- -

ATXN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATXN1 p.Gln208del variant was not identified in the literature but was identified in dbSNP (ID: rs797045409) with cliinical significance as "With uncertain significance allele", Cosmic, LOVD 3.0 and ClinVar (classified as a VUS by the University of Chicago). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. MutationTaster predicts the variant to be a polymorphism. This variant is an in-frame deletion of CAG resulting in the removal of a Glutamine residue at codon 208; this deletion occurs within the CAG repeat region known to cause spinocerebellar ataxia type 1. As this variant is still within the normal repeat range, it is unlikely to have any damaging effect. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lead towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922926; hg19: chr6-16327915;