NM_001128164.2:c.591_626dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

• chr6-16327684-A-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC
• rs193922926
• NM_001128164.2:c.591_626dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001128164.2(ATXN1):​c.591_626dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA​(p.Gln197_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 0.0000074 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0000037 (0 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, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001128164.2

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.591_626dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln197_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	NP_001121636.1
	ATXN1	NM_000332.4		c.591_626dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln197_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	NP_000323.2
	ATXN1	NM_001357857.2		c.*4_*39dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA		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.591_626dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln197_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	ENSP00000416360.1
	ATXN1	ENST00000244769.8	TSL:1	c.591_626dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln197_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	ENSP00000244769.3
	ATXN1	ENST00000642969.1		c.*4_*39dupGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA		downstream_gene	N/A	ENSP00000493530.1

Frequencies

GnomAD3 genomes AF: 0.00000743 AC: 1 AN: 134644 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000253

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000373 AC: 5 AN: 1339462 Hom.: 0 Cov.: 32 AF XY: 0.00000601 AC XY: 4 AN XY: 665480

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26546

American (AMR) AF: 0.00 AC: 0 AN: 35508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24870

East Asian (EAS) AF: 0.00 AC: 0 AN: 30604

South Asian (SAS) AF: 0.0000537 AC: 4 AN: 74458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4600

European-Non Finnish (NFE) AF: 9.55e-7 AC: 1 AN: 1047598

Other (OTH) AF: 0.00 AC: 0 AN: 55068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00276055), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000743 AC: 1 AN: 134644 Hom.: 0 Cov.: 20 AF XY: 0.0000153 AC XY: 1 AN XY: 65412

African (AFR) AF: 0.00 AC: 0 AN: 32724

American (AMR) AF: 0.00 AC: 0 AN: 13302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3278

East Asian (EAS) AF: 0.00 AC: 0 AN: 4042

South Asian (SAS) AF: 0.000253 AC: 1 AN: 3958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64568

Other (OTH) AF: 0.00 AC: 0 AN: 1816

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;