6-16327684-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-ATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant names:

• chr6-16327684-A-ATGCTGCTGCTGC
• rs193922926
• NM_001128164.2:c.615_626dupGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_001128164.2(ATXN1):​c.615_626dupGCAGCAGCAGCA​(p.Gln205_Gln208dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 20)
  • Exomes 𝑓: 0.0026 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN1 NM_001128164.2 disruptive_inframe_insertion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001128164.2
• 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 VariationId is 3060614.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 669 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_626dupGCAGCAGCAGCA	p.Gln205_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.615_626dupGCAGCAGCAGCA	p.Gln205_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.*28_*39dupGCAGCAGCAGCA		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_626dupGCAGCAGCAGCA	p.Gln205_Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.615_626dupGCAGCAGCAGCA	p.Gln205_Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000642969.1		c.*28_*39dupGCAGCAGCAGCA		downstream_gene	N/A	ENSP00000493530.1	A0A2R8YCF3

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

African (AFR) AF: 0.00432 AC: 114 AN: 26390

American (AMR) AF: 0.00254 AC: 90 AN: 35462

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 384 AN: 24480

East Asian (EAS) AF: 0.00101 AC: 31 AN: 30600

South Asian (SAS) AF: 0.00262 AC: 195 AN: 74366

European-Finnish (FIN) AF: 0.00125 AC: 50 AN: 40152

Middle Eastern (MID) AF: 0.000218 AC: 1 AN: 4590

European-Non Finnish (NFE) AF: 0.00227 AC: 2374 AN: 1044496

Other (OTH) AF: 0.00384 AC: 211 AN: 54904

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

African (AFR) AF: 0.00755 AC: 248 AN: 32832

American (AMR) AF: 0.00323 AC: 43 AN: 13312

Ashkenazi Jewish (ASJ) AF: 0.0281 AC: 92 AN: 3278

East Asian (EAS) AF: 0.000745 AC: 3 AN: 4028

South Asian (SAS) AF: 0.00430 AC: 17 AN: 3956

European-Finnish (FIN) AF: 0.000509 AC: 5 AN: 9816

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

European-Non Finnish (NFE) AF: 0.00393 AC: 254 AN: 64556

Other (OTH) AF: 0.00382 AC: 7 AN: 1834

Alfa AF: 0.00 Hom.: 48

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ATXN1-related disorder (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;