6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Position:

• chr6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001128164.2(ATXN1):​c.626_627insGCA​(p.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 0.15 (1525 hom., cov: 20)
  • Exomes 𝑓: 0.10 (4563 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN1 NM_001128164.2 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -16 ACMG points.

• BP6: Variant 6-16327684-A-ATGC is Benign according to our data. Variant chr6-16327684-A-ATGC is described in ClinVar as [Likely_benign]. Clinvar id is 218439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.626_627insGCA	p.Gln208dup	inframe_insertion	7/8	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.626_627insGCA	p.Gln208dup	inframe_insertion	8/9		NP_000323.2
ATXN1	NM_001357857.2	c.*39_*40insGCA		3_prime_UTR_variant	8/9		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.626_627insGCA	p.Gln208dup	inframe_insertion	7/8	1	NM_001128164.2	ENSP00000416360	P1
ATXN1	ENST00000244769.8	c.626_627insGCA	p.Gln208dup	inframe_insertion	8/9	1		ENSP00000244769	P1
ATXN1	ENST00000642969.1			downstream_gene_variant				ENSP00000493530

Frequencies

GnomAD3 genomes AF: 0.151 AC: 20197 AN: 133820 Hom.: 1522 Cov.: 20

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0597

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0860

Gnomad MID AF: 0.176

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.157

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.101 AC: 129320 AN: 1276998 Hom.: 4563 Cov.: 32 AF XY: 0.102 AC XY: 64526 AN XY: 634658

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.0887

Gnomad4 EAS exome AF: 0.0644

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.0861

Gnomad4 NFE exome AF: 0.0986

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.151 AC: 20219 AN: 133914 Hom.: 1525 Cov.: 20 AF XY: 0.148 AC XY: 9662 AN XY: 65072

Gnomad4 AFR AF: 0.240

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.0596

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0860

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.155

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 10, 2015

- -

ATXN1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 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). -

Spinocerebellar ataxia type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

May 17, 2017

- -

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;