6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant names:

• chr6-16327684-A-ATGCTGCTGC
• rs193922926
• NM_001128164.2:c.618_626dupGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 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
• Publications: 0 publications found

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)

ACMG classification

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

• BP3: Nonframeshift variant in repetitive region in NM_001128164.2
• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3970 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128164.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	NM_001128164.2	MANE Select	c.618_626dupGCAGCAGCA	p.Gln206_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	NP_001121636.1
	ATXN1	NM_000332.4		c.618_626dupGCAGCAGCA	p.Gln206_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	NP_000323.2
	ATXN1	NM_001357857.2		c.*31_*39dupGCAGCAGCA		3_prime_UTR	Exon 8 of 9	NP_001344786.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	ENST00000436367.6	TSL:1 MANE Select	c.618_626dupGCAGCAGCA	p.Gln206_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	ENSP00000416360.1
	ATXN1	ENST00000244769.8	TSL:1	c.618_626dupGCAGCAGCA	p.Gln206_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	ENSP00000244769.3
	ATXN1	ENST00000642969.1		c.*31_*39dupGCAGCAGCA		downstream_gene	N/A	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

African (AFR) AF: 0.0253 AC: 656 AN: 25928

American (AMR) AF: 0.0103 AC: 363 AN: 35306

Ashkenazi Jewish (ASJ) AF: 0.0178 AC: 439 AN: 24654

East Asian (EAS) AF: 0.00173 AC: 53 AN: 30596

South Asian (SAS) AF: 0.0126 AC: 932 AN: 74212

European-Finnish (FIN) AF: 0.0319 AC: 1276 AN: 40058

Middle Eastern (MID) AF: 0.00612 AC: 28 AN: 4576

European-Non Finnish (NFE) AF: 0.0156 AC: 16094 AN: 1029742

Other (OTH) AF: 0.0163 AC: 890 AN: 54500

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

African (AFR) AF: 0.0426 AC: 1398 AN: 32786

American (AMR) AF: 0.0162 AC: 216 AN: 13310

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 84 AN: 3278

East Asian (EAS) AF: 0.00124 AC: 5 AN: 4026

South Asian (SAS) AF: 0.0144 AC: 57 AN: 3954

European-Finnish (FIN) AF: 0.0412 AC: 404 AN: 9806

Middle Eastern (MID) AF: 0.00775 AC: 2 AN: 258

European-Non Finnish (NFE) AF: 0.0272 AC: 1757 AN: 64538

Other (OTH) AF: 0.0240 AC: 44 AN: 1832

Alfa AF: 0.0225 Hom.: 48

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ATXN1-related disorder Benign:1

Mar 11, 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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11
Mutation Taster		=91/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs193922926; hg19: chr6-16327915;