6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Position:

• chr6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001128164.2(ATXN1):​c.626_627insGCAGCAGCAGCA​(p.Gln205_Gln208dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 20)
  • Exomes 𝑓: 0.0026 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN1 NM_001128164.2 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -6 ACMG points.

• BP6: Variant 6-16327684-A-ATGCTGCTGCTGC is Benign according to our data. Variant chr6-16327684-A-ATGCTGCTGCTGC is described in ClinVar as [Likely_benign]. Clinvar id is 3060614.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 669 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.626_627insGCAGCAGCAGCA	p.Gln205_Gln208dup	inframe_insertion	7/8	ENST00000436367.6
ATXN1	NM_000332.4	c.626_627insGCAGCAGCAGCA	p.Gln205_Gln208dup	inframe_insertion	8/9
ATXN1	NM_001357857.2	c.*39_*40insGCAGCAGCAGCA		3_prime_UTR_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.626_627insGCAGCAGCAGCA	p.Gln205_Gln208dup	inframe_insertion	7/8	1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.626_627insGCAGCAGCAGCA	p.Gln205_Gln208dup	inframe_insertion	8/9	1		P1
ATXN1	ENST00000642969.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 668 AN: 134636 Hom.: 4 Cov.: 20

Gnomad AFR AF: 0.00755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00323

Gnomad ASJ AF: 0.0281

Gnomad EAS AF: 0.000742

Gnomad SAS AF: 0.00430

Gnomad FIN AF: 0.000509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00385

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00258 AC: 3450 AN: 1335440 Hom.: 5 Cov.: 32 AF XY: 0.00265 AC XY: 1760 AN XY: 663574

Gnomad4 AFR exome AF: 0.00432

Gnomad4 AMR exome AF: 0.00254

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00497 AC: 669 AN: 134734 Hom.: 4 Cov.: 20 AF XY: 0.00489 AC XY: 320 AN XY: 65504

Gnomad4 AFR AF: 0.00755

Gnomad4 AMR AF: 0.00323

Gnomad4 ASJ AF: 0.0281

Gnomad4 EAS AF: 0.000745

Gnomad4 SAS AF: 0.00430

Gnomad4 FIN AF: 0.000509

Gnomad4 NFE AF: 0.00393

Gnomad4 OTH AF: 0.00382

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ATXN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;