6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant names:

• chr6-16327684-A-ATGCTGC
• rs193922926
• NM_001128164.2:c.621_626dupGCAGCA

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_001128164.2(ATXN1):​c.621_626dupGCAGCA​(p.Gln207_Gln208dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.089 (573 hom., cov: 20)
  • Exomes 𝑓: 0.059 (2232 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN1 NM_001128164.2 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.106
• 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: Benign. The variant received -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001128164.2
• BP6: Variant 6-16327684-A-ATGCTGC is Benign according to our data. Variant chr6-16327684-A-ATGCTGC is described in ClinVar as Likely_benign. ClinVar VariationId is 3057230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

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.621_626dupGCAGCA	p.Gln207_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.621_626dupGCAGCA	p.Gln207_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.*34_*39dupGCAGCA		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.621_626dupGCAGCA	p.Gln207_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.621_626dupGCAGCA	p.Gln207_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000642969.1		c.*34_*39dupGCAGCA		downstream_gene	N/A	ENSP00000493530.1	A0A2R8YCF3

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 11926 AN: 134478 Hom.: 569 Cov.: 20

Gnomad AFR AF: 0.0965

Gnomad AMI AF: 0.0394

Gnomad AMR AF: 0.0992

Gnomad ASJ AF: 0.0324

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0969

Gnomad MID AF: 0.0761

Gnomad NFE AF: 0.0881

Gnomad OTH AF: 0.0937

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0587 AC: 75114 AN: 1278760 Hom.: 2232 Cov.: 32 AF XY: 0.0592 AC XY: 37641 AN XY: 635340

African (AFR) AF: 0.0686 AC: 1747 AN: 25478

American (AMR) AF: 0.0703 AC: 2417 AN: 34370

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 495 AN: 24468

East Asian (EAS) AF: 0.00680 AC: 208 AN: 30578

South Asian (SAS) AF: 0.0861 AC: 6203 AN: 72076

European-Finnish (FIN) AF: 0.0836 AC: 3317 AN: 39678

Middle Eastern (MID) AF: 0.0377 AC: 169 AN: 4486

European-Non Finnish (NFE) AF: 0.0577 AC: 57407 AN: 994388

Other (OTH) AF: 0.0592 AC: 3151 AN: 53238

GnomAD4 genome AF: 0.0887 AC: 11934 AN: 134576 Hom.: 573 Cov.: 20 AF XY: 0.0895 AC XY: 5855 AN XY: 65426

African (AFR) AF: 0.0962 AC: 3154 AN: 32772

American (AMR) AF: 0.0999 AC: 1329 AN: 13302

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 106 AN: 3276

East Asian (EAS) AF: 0.0104 AC: 42 AN: 4026

South Asian (SAS) AF: 0.113 AC: 446 AN: 3950

European-Finnish (FIN) AF: 0.0969 AC: 950 AN: 9802

Middle Eastern (MID) AF: 0.0659 AC: 17 AN: 258

European-Non Finnish (NFE) AF: 0.0881 AC: 5682 AN: 64494

Other (OTH) AF: 0.0950 AC: 174 AN: 1832

Alfa AF: 0.0465 Hom.: 48

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ATXN1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11
Mutation Taster		=91/9	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; COSMIC: COSV55214920; COSMIC: COSV55214920;