chr6-16327684-ATGCTGCTGCTGC-A

Variant names:

• chr6-16327684-ATGCTGCTGCTGC-A
• rs193922926
• NM_001128164.2:c.615_626delGCAGCAGCAGCA

Variant summary

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

The NM_001128164.2(ATXN1):​c.615_626delGCAGCAGCAGCA​(p.Gln205_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 0.000202 in 1,474,032 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.00061 (1 hom., cov: 20)
  • Exomes 𝑓: 0.00016 (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, 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 82 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.615_626delGCAGCAGCAGCA	p.Gln205_Gln208del	disruptive_inframe_deletion	Exon 7 of 8	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.615_626delGCAGCAGCAGCA	p.Gln205_Gln208del	disruptive_inframe_deletion	Exon 8 of 9	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.*28_*39delGCAGCAGCAGCA		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.615_626delGCAGCAGCAGCA	p.Gln205_Gln208del	disruptive_inframe_deletion	Exon 7 of 8	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.615_626delGCAGCAGCAGCA	p.Gln205_Gln208del	disruptive_inframe_deletion	Exon 8 of 9	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000642969.1		c.*28_*39delGCAGCAGCAGCA		downstream_gene	N/A	ENSP00000493530.1	A0A2R8YCF3

Frequencies

GnomAD3 genomes AF: 0.000609 AC: 82 AN: 134636 Hom.: 1 Cov.: 20

Gnomad AFR AF: 0.00144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000902

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00272

Gnomad SAS AF: 0.000758

Gnomad FIN AF: 0.000204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000929

Gnomad OTH AF: 0.000551

GnomAD4 exome AF: 0.000161 AC: 216 AN: 1339298 Hom.: 0 AF XY: 0.000173 AC XY: 115 AN XY: 665408

African (AFR) AF: 0.000603 AC: 16 AN: 26532

American (AMR) AF: 0.000423 AC: 15 AN: 35500

Ashkenazi Jewish (ASJ) AF: 0.0000402 AC: 1 AN: 24870

East Asian (EAS) AF: 0.00226 AC: 69 AN: 30584

South Asian (SAS) AF: 0.000242 AC: 18 AN: 74458

European-Finnish (FIN) AF: 0.0000249 AC: 1 AN: 40210

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

European-Non Finnish (NFE) AF: 0.0000802 AC: 84 AN: 1047484

Other (OTH) AF: 0.000218 AC: 12 AN: 55060

GnomAD4 genome AF: 0.000609 AC: 82 AN: 134734 Hom.: 1 Cov.: 20 AF XY: 0.000565 AC XY: 37 AN XY: 65504

African (AFR) AF: 0.00143 AC: 47 AN: 32832

American (AMR) AF: 0.000901 AC: 12 AN: 13312

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

East Asian (EAS) AF: 0.00273 AC: 11 AN: 4028

South Asian (SAS) AF: 0.000758 AC: 3 AN: 3956

European-Finnish (FIN) AF: 0.000204 AC: 2 AN: 9816

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

European-Non Finnish (NFE) AF: 0.0000929 AC: 6 AN: 64556

Other (OTH) AF: 0.000545 AC: 1 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;