6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BA1

The NM_001128164.2(ATXN1):c.624_626delGCA(p.Gln208del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.045 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.123

Publications

0 publications found

Variant links:

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]

ATXN1 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 1
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ATXN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001128164.2

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 VariationId is 210503.

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 rank	MANE	Protein
ATXN1	NM_001128164.2 link	c.624_626delGCA	p.Gln208del	disruptive_inframe_deletion	Exon 7 of 8	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4 link	c.624_626delGCA	p.Gln208del	disruptive_inframe_deletion	Exon 8 of 9		NP_000323.2
ATXN1	NM_001357857.2 link	c.37_39delGCA		3_prime_UTR_variant	Exon 8 of 9		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ATXN1	ENST00000436367.6 link	c.624_626delGCA	p.Gln208del	disruptive_inframe_deletion	Exon 7 of 8	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8 link	c.624_626delGCA	p.Gln208del	disruptive_inframe_deletion	Exon 8 of 9	1		ENSP00000244769.3
ATXN1	ENST00000642969.1 link	c.37_39delGCA		downstream_gene_variant				ENSP00000493530.1

Frequencies

GnomAD3 genomes

AF:

0.0695

AC:

9320

AN:

134190

Hom.:

522

Cov.:

show subpopulations

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

show subpopulations

African (AFR)

AF:

0.0367

AC:

950

AN:

25878

American (AMR)

AF:

0.101

AC:

3302

AN:

32708

Ashkenazi Jewish (ASJ)

AF:

0.0204

AC:

498

AN:

24380

East Asian (EAS)

AF:

0.344

AC:

10401

AN:

30196

South Asian (SAS)

AF:

0.107

AC:

7595

AN:

70900

European-Finnish (FIN)

AF:

0.0672

AC:

2657

AN:

39526

Middle Eastern (MID)

AF:

0.0337

AC:

152

AN:

4510

European-Non Finnish (NFE)

AF:

0.0262

AC:

26748

AN:

1019624

Other (OTH)

AF:

0.0548

AC:

2932

AN:

53472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.406

Heterozygous variant carriers

2009

4018

6027

8036

10045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1016

2032

3048

4064

5080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0694

AC:

9315

AN:

134288

Hom.:

522

Cov.:

AF XY:

0.0744

AC XY:

4853

AN XY:

65272

show subpopulations

African (AFR)

AF:

0.0558

AC:

1827

AN:

32716

American (AMR)

AF:

0.124

AC:

1643

AN:

13242

Ashkenazi Jewish (ASJ)

AF:

0.0327

AC:

107

AN:

3274

East Asian (EAS)

AF:

0.372

AC:

1489

AN:

4008

South Asian (SAS)

AF:

0.144

AC:

567

AN:

3932

European-Finnish (FIN)

AF:

0.0848

AC:

828

AN:

9768

Middle Eastern (MID)

AF:

0.0426

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.0397

AC:

2558

AN:

64414

Other (OTH)

AF:

0.0626

AC:

114

AN:

1820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

314

628

943

1257

1571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0212

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

ATXN1-related disorder

Benign:1

Jul 02, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.12

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over