NM_001128164.2:c.609_626dupGCAGCAGCAGCAGCAGCA

Variant names:

• chr6-16327684-A-ATGCTGCTGCTGCTGCTGC
• rs193922926
• NM_001128164.2:c.609_626dupGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001128164.2(ATXN1):​c.609_626dupGCAGCAGCAGCAGCAGCA​(p.Gln203_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 0.0034 (4 hom., cov: 20)
  • Exomes 𝑓: 0.0012 (4 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: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001128164.2
• BS2: High AC in GnomAd4 at 458 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.609_626dupGCAGCAGCAGCAGCAGCA	p.Gln203_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.609_626dupGCAGCAGCAGCAGCAGCA	p.Gln203_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.*22_*39dupGCAGCAGCAGCAGCAGCA		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.609_626dupGCAGCAGCAGCAGCAGCA	p.Gln203_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.609_626dupGCAGCAGCAGCAGCAGCA	p.Gln203_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000642969.1		c.*22_*39dupGCAGCAGCAGCAGCAGCA		downstream_gene	N/A	ENSP00000493530.1	A0A2R8YCF3

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 458 AN: 134632 Hom.: 4 Cov.: 20

Gnomad AFR AF: 0.00807

Gnomad AMI AF: 0.0266

Gnomad AMR AF: 0.000601

Gnomad ASJ AF: 0.00427

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00328

Gnomad FIN AF: 0.000509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00195

Gnomad OTH AF: 0.00275

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00120 AC: 1599 AN: 1337988 Hom.: 4 Cov.: 32 AF XY: 0.00128 AC XY: 848 AN XY: 664820

African (AFR) AF: 0.00601 AC: 159 AN: 26434

American (AMR) AF: 0.000423 AC: 15 AN: 35498

Ashkenazi Jewish (ASJ) AF: 0.00242 AC: 60 AN: 24842

East Asian (EAS) AF: 0.0000980 AC: 3 AN: 30598

South Asian (SAS) AF: 0.00290 AC: 216 AN: 74372

European-Finnish (FIN) AF: 0.000597 AC: 24 AN: 40208

Middle Eastern (MID) AF: 0.000217 AC: 1 AN: 4600

European-Non Finnish (NFE) AF: 0.00100 AC: 1048 AN: 1046412

Other (OTH) AF: 0.00133 AC: 73 AN: 55024

GnomAD4 genome AF: 0.00340 AC: 458 AN: 134730 Hom.: 4 Cov.: 20 AF XY: 0.00344 AC XY: 225 AN XY: 65502

African (AFR) AF: 0.00804 AC: 264 AN: 32824

American (AMR) AF: 0.000601 AC: 8 AN: 13314

Ashkenazi Jewish (ASJ) AF: 0.00427 AC: 14 AN: 3278

East Asian (EAS) AF: 0.00 AC: 0 AN: 4028

South Asian (SAS) AF: 0.00329 AC: 13 AN: 3956

European-Finnish (FIN) AF: 0.000509 AC: 5 AN: 9816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.00195 AC: 126 AN: 64558

Other (OTH) AF: 0.00273 AC: 5 AN: 1834

Alfa AF: 0.00 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;