6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant names:

• chr6-16327684-A-ATGCTGCTGCTGCTGC
• rs193922926
• NM_001128164.2:c.612_626dupGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_001128164.2(ATXN1):​c.612_626dupGCAGCAGCAGCAGCA​(p.Gln204_Gln208dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.019 (36 hom., cov: 20)
  • Exomes 𝑓: 0.014 (146 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN1 NM_001128164.2 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001128164.2
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0189 (2541/134688) while in subpopulation NFE AF = 0.0233 (1504/64538). AF 95% confidence interval is 0.0223. There are 36 homozygotes in GnomAd4. There are 1279 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2541 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	NM_001128164.2	MANE Select	c.612_626dupGCAGCAGCAGCAGCA	p.Gln204_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.612_626dupGCAGCAGCAGCAGCA	p.Gln204_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.*25_*39dupGCAGCAGCAGCAGCA		3_prime_UTR	Exon 8 of 9	NP_001344786.1	A0A2R8YCF3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	ENST00000436367.6	TSL:1 MANE Select	c.612_626dupGCAGCAGCAGCAGCA	p.Gln204_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.612_626dupGCAGCAGCAGCAGCA	p.Gln204_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000642969.1		c.*25_*39dupGCAGCAGCAGCAGCA		downstream_gene	N/A	ENSP00000493530.1	A0A2R8YCF3

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2542 AN: 134590 Hom.: 36 Cov.: 20

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00579

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0119

Gnomad EAS AF: 0.000247

Gnomad SAS AF: 0.00960

Gnomad FIN AF: 0.0352

Gnomad MID AF: 0.0109

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0132

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0138 AC: 18289 AN: 1323104 Hom.: 146 Cov.: 32 AF XY: 0.0135 AC XY: 8902 AN XY: 657492

African (AFR) AF: 0.00842 AC: 222 AN: 26352

American (AMR) AF: 0.00448 AC: 159 AN: 35454

Ashkenazi Jewish (ASJ) AF: 0.00765 AC: 189 AN: 24706

East Asian (EAS) AF: 0.000784 AC: 24 AN: 30594

South Asian (SAS) AF: 0.00938 AC: 696 AN: 74220

European-Finnish (FIN) AF: 0.0333 AC: 1336 AN: 40086

Middle Eastern (MID) AF: 0.00743 AC: 34 AN: 4574

European-Non Finnish (NFE) AF: 0.0144 AC: 14878 AN: 1032544

Other (OTH) AF: 0.0138 AC: 751 AN: 54574

GnomAD4 genome AF: 0.0189 AC: 2541 AN: 134688 Hom.: 36 Cov.: 20 AF XY: 0.0195 AC XY: 1279 AN XY: 65476

African (AFR) AF: 0.0137 AC: 448 AN: 32812

American (AMR) AF: 0.0101 AC: 134 AN: 13314

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 39 AN: 3278

East Asian (EAS) AF: 0.000248 AC: 1 AN: 4028

South Asian (SAS) AF: 0.00961 AC: 38 AN: 3956

European-Finnish (FIN) AF: 0.0352 AC: 345 AN: 9808

Middle Eastern (MID) AF: 0.0116 AC: 3 AN: 258

European-Non Finnish (NFE) AF: 0.0233 AC: 1504 AN: 64538

Other (OTH) AF: 0.0131 AC: 24 AN: 1832

Alfa AF: 0.00239 Hom.: 48

ClinVar

Not reported in ClinVar

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; COSMIC: COSV106051791; COSMIC: COSV106051791;