6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001128164.2(ATXN1):c.626_627insGCAGCA(p.Gln207_Gln208dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.089 (573 hom., cov: 20)
  • Exomes 𝑓: 0.059 (2232 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN1 NM_001128164.2 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.106

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 -10 ACMG points.

• BP6: Variant 6-16327684-A-ATGCTGC is Benign according to our data. Variant chr6-16327684-A-ATGCTGC is described in ClinVar as [Likely_benign]. Clinvar id is 3057230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.626_627insGCAGCA	p.Gln207_Gln208dup	inframe_insertion	7/8	ENST00000436367.6
ATXN1	NM_000332.4	c.626_627insGCAGCA	p.Gln207_Gln208dup	inframe_insertion	8/9
ATXN1	NM_001357857.2	c.*39_*40insGCAGCA		3_prime_UTR_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.626_627insGCAGCA	p.Gln207_Gln208dup	inframe_insertion	7/8	1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.626_627insGCAGCA	p.Gln207_Gln208dup	inframe_insertion	8/9	1		P1
ATXN1	ENST00000642969.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 11926 AN: 134478 Hom.: 569 Cov.: 20

Gnomad AFR AF: 0.0965

Gnomad AMI AF: 0.0394

Gnomad AMR AF: 0.0992

Gnomad ASJ AF: 0.0324

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0969

Gnomad MID AF: 0.0761

Gnomad NFE AF: 0.0881

Gnomad OTH AF: 0.0937

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0587 AC: 75114 AN: 1278760 Hom.: 2232 Cov.: 32 AF XY: 0.0592 AC XY: 37641 AN XY: 635340

Gnomad4 AFR exome AF: 0.0686

Gnomad4 AMR exome AF: 0.0703

Gnomad4 ASJ exome AF: 0.0202

Gnomad4 EAS exome AF: 0.00680

Gnomad4 SAS exome AF: 0.0861

Gnomad4 FIN exome AF: 0.0836

Gnomad4 NFE exome AF: 0.0577

Gnomad4 OTH exome AF: 0.0592

GnomAD4 genome AF: 0.0887 AC: 11934 AN: 134576 Hom.: 573 Cov.: 20 AF XY: 0.0895 AC XY: 5855 AN XY: 65426

Gnomad4 AFR AF: 0.0962

Gnomad4 AMR AF: 0.0999

Gnomad4 ASJ AF: 0.0324

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0969

Gnomad4 NFE AF: 0.0881

Gnomad4 OTH AF: 0.0950

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ATXN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 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). -

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: rs193922926; hg19: chr6-16327915;