6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGC

Variant names:

• chr6-16327684-ATGCTGC-A
• rs193922926
• NM_001128164.2:c.621_626delGCAGCA

Variant summary

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

The NM_001128164.2(ATXN1):​c.621_626delGCAGCA​(p.Gln207_Gln208del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 20)
  • Exomes 𝑓: 0.00045 (2 hom.)
  • Failed GnomAD Quality Control
• 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 439 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.621_626delGCAGCA	p.Gln207_Gln208del	disruptive_inframe_deletion	Exon 7 of 8	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.621_626delGCAGCA	p.Gln207_Gln208del	disruptive_inframe_deletion	Exon 8 of 9		NP_000323.2
ATXN1	NM_001357857.2	c.*34_*39delGCAGCA		3_prime_UTR_variant	Exon 8 of 9		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.621_626delGCAGCA	p.Gln207_Gln208del	disruptive_inframe_deletion	Exon 7 of 8	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.621_626delGCAGCA	p.Gln207_Gln208del	disruptive_inframe_deletion	Exon 8 of 9	1		ENSP00000244769.3
ATXN1	ENST00000642969.1	c.*34_*39delGCAGCA		downstream_gene_variant				ENSP00000493530.1

Frequencies

GnomAD3 genomes AF: 0.00322 AC: 434 AN: 134614 Hom.: 4 Cov.: 20

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00128

Gnomad ASJ AF: 0.000305

Gnomad EAS AF: 0.00148

Gnomad SAS AF: 0.00152

Gnomad FIN AF: 0.000204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000465

Gnomad OTH AF: 0.00110

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000445 AC: 596 AN: 1338174 Hom.: 2 AF XY: 0.000435 AC XY: 289 AN XY: 664824

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

African (AFR) AF: 0.00924 AC: 244 AN: 26396

American (AMR) AF: 0.000678 AC: 24 AN: 35416

Ashkenazi Jewish (ASJ) AF: 0.0000402 AC: 1 AN: 24866

East Asian (EAS) AF: 0.000667 AC: 20 AN: 29992

South Asian (SAS) AF: 0.00137 AC: 102 AN: 74354

European-Finnish (FIN) AF: 0.000199 AC: 8 AN: 40172

Middle Eastern (MID) AF: 0.00130 AC: 6 AN: 4598

European-Non Finnish (NFE) AF: 0.000128 AC: 134 AN: 1047382

Other (OTH) AF: 0.00104 AC: 57 AN: 54998

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00326 AC: 439 AN: 134710 Hom.: 4 Cov.: 20 AF XY: 0.00311 AC XY: 204 AN XY: 65498

African (AFR) AF: 0.0114 AC: 375 AN: 32806

American (AMR) AF: 0.00128 AC: 17 AN: 13314

Ashkenazi Jewish (ASJ) AF: 0.000305 AC: 1 AN: 3278

East Asian (EAS) AF: 0.00149 AC: 6 AN: 4028

South Asian (SAS) AF: 0.00152 AC: 6 AN: 3956

European-Finnish (FIN) AF: 0.000204 AC: 2 AN: 9814

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

European-Non Finnish (NFE) AF: 0.000465 AC: 30 AN: 64558

Other (OTH) AF: 0.00109 AC: 2 AN: 1834

Alfa AF: 0.0413 Hom.: 48

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
Mutation Taster		=182/18	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;