6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGC

Variant names:

• chr6-16327684-ATGCTGCTGC-A
• rs193922926
• NM_001128164.2:c.618_626delGCAGCAGCA

Variant summary

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

The NM_001128164.2(ATXN1):​c.618_626delGCAGCAGCA​(p.Gln206_Gln208del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,473,954 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: ATXN1 NM_001128164.2 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123
• 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 -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001128164.2
• BS2: High AC in GnomAd4 at 36 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_626delGCAGCAGCA	p.Gln206_Gln208del	disruptive_inframe_deletion	Exon 7 of 8	NP_001121636.1
	ATXN1	NM_000332.4		c.618_626delGCAGCAGCA	p.Gln206_Gln208del	disruptive_inframe_deletion	Exon 8 of 9	NP_000323.2
	ATXN1	NM_001357857.2		c.*31_*39delGCAGCAGCA		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_626delGCAGCAGCA	p.Gln206_Gln208del	disruptive_inframe_deletion	Exon 7 of 8	ENSP00000416360.1
	ATXN1	ENST00000244769.8	TSL:1	c.618_626delGCAGCAGCA	p.Gln206_Gln208del	disruptive_inframe_deletion	Exon 8 of 9	ENSP00000244769.3
	ATXN1	ENST00000642969.1		c.*31_*39delGCAGCAGCA		downstream_gene	N/A	ENSP00000493530.1

Frequencies

GnomAD3 genomes AF: 0.000260 AC: 35 AN: 134640 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000526

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000495

Gnomad SAS AF: 0.000505

Gnomad FIN AF: 0.000102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000124

Gnomad OTH AF: 0.00165

GnomAD4 exome AF: 0.0000904 AC: 121 AN: 1339216 Hom.: 0 AF XY: 0.0000857 AC XY: 57 AN XY: 665378

African (AFR) AF: 0.000490 AC: 13 AN: 26532

American (AMR) AF: 0.000366 AC: 13 AN: 35508

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

East Asian (EAS) AF: 0.000425 AC: 13 AN: 30604

South Asian (SAS) AF: 0.0000806 AC: 6 AN: 74462

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

Middle Eastern (MID) AF: 0.000652 AC: 3 AN: 4598

European-Non Finnish (NFE) AF: 0.0000420 AC: 44 AN: 1047376

Other (OTH) AF: 0.000527 AC: 29 AN: 55056

GnomAD4 genome AF: 0.000267 AC: 36 AN: 134738 Hom.: 0 Cov.: 20 AF XY: 0.000305 AC XY: 20 AN XY: 65508

African (AFR) AF: 0.000396 AC: 13 AN: 32832

American (AMR) AF: 0.000526 AC: 7 AN: 13314

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

East Asian (EAS) AF: 0.000497 AC: 2 AN: 4028

South Asian (SAS) AF: 0.000506 AC: 2 AN: 3956

European-Finnish (FIN) AF: 0.000102 AC: 1 AN: 9816

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

European-Non Finnish (NFE) AF: 0.000124 AC: 8 AN: 64558

Other (OTH) AF: 0.00164 AC: 3 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		0.12
Mutation Taster		=193/7	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;