chr6-16327684-A-ATGCTGCTGCTGCTGCTGC

Position:

• chr6-16327684-A-ATGCTGCTGCTGCTGCTGC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. 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. 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 458 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.609_626dupGCAGCAGCAGCAGCAGCA	p.Gln203_Gln208dup	disruptive_inframe_insertion	7/8	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.609_626dupGCAGCAGCAGCAGCAGCA	p.Gln203_Gln208dup	disruptive_inframe_insertion	8/9		NP_000323.2
ATXN1	NM_001357857.2	c.*22_*39dupGCAGCAGCAGCAGCAGCA		3_prime_UTR_variant	8/9		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.609_626dupGCAGCAGCAGCAGCAGCA	p.Gln203_Gln208dup	disruptive_inframe_insertion	7/8	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.609_626dupGCAGCAGCAGCAGCAGCA	p.Gln203_Gln208dup	disruptive_inframe_insertion	8/9	1		ENSP00000244769.3
ATXN1	ENST00000642969.1	c.*22_*39dupGCAGCAGCAGCAGCAGCA		downstream_gene_variant				ENSP00000493530.1

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

Gnomad4 AFR exome AF: 0.00601

Gnomad4 AMR exome AF: 0.000423

Gnomad4 ASJ exome AF: 0.00242

Gnomad4 EAS exome AF: 0.0000980

Gnomad4 SAS exome AF: 0.00290

Gnomad4 FIN exome AF: 0.000597

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.00133

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

Gnomad4 AFR AF: 0.00804

Gnomad4 AMR AF: 0.000601

Gnomad4 ASJ AF: 0.00427

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00329

Gnomad4 FIN AF: 0.000509

Gnomad4 NFE AF: 0.00195

Gnomad4 OTH AF: 0.00273

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922926; hg19: chr6-16327915;