6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Position:

• chr6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001128164.2(ATXN1):​c.618_626dupGCAGCAGCA​(p.Gln206_Gln208dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.029 (58 hom., cov: 20)
  • Exomes 𝑓: 0.016 (168 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN1 NM_001128164.2 disruptive_inframe_insertion
• Clinical Significance: Likely benign no assertion criteria provided 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 -9 ACMG points.

• BP6: Variant 6-16327684-A-ATGCTGCTGC is Benign according to our data. Variant chr6-16327684-A-ATGCTGCTGC is described in ClinVar as [Likely_benign]. Clinvar id is 3059363.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0295 (3970/134652) while in subpopulation AFR AF= 0.0426 (1398/32786). AF 95% confidence interval is 0.0408. There are 58 homozygotes in gnomad4. There are 1917 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3970 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.618_626dupGCAGCAGCA	p.Gln206_Gln208dup	disruptive_inframe_insertion	7/8	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.618_626dupGCAGCAGCA	p.Gln206_Gln208dup	disruptive_inframe_insertion	8/9		NP_000323.2
ATXN1	NM_001357857.2	c.*31_*39dupGCAGCAGCA		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.618_626dupGCAGCAGCA	p.Gln206_Gln208dup	disruptive_inframe_insertion	7/8	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.618_626dupGCAGCAGCA	p.Gln206_Gln208dup	disruptive_inframe_insertion	8/9	1		ENSP00000244769.3
ATXN1	ENST00000642969.1	c.*31_*39dupGCAGCAGCA		downstream_gene_variant				ENSP00000493530.1

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 3963 AN: 134552 Hom.: 58 Cov.: 20

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.00347

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.00124

Gnomad SAS AF: 0.0142

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.00725

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0237

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0157 AC: 20731 AN: 1319572 Hom.: 168 Cov.: 32 AF XY: 0.0156 AC XY: 10256 AN XY: 656110

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0178

Gnomad4 EAS exome AF: 0.00173

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.0319

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0295 AC: 3970 AN: 134652 Hom.: 58 Cov.: 20 AF XY: 0.0293 AC XY: 1917 AN XY: 65462

Gnomad4 AFR AF: 0.0426

Gnomad4 AMR AF: 0.0162

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.00124

Gnomad4 SAS AF: 0.0144

Gnomad4 FIN AF: 0.0412

Gnomad4 NFE AF: 0.0272

Gnomad4 OTH AF: 0.0240

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

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). -

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;