NM_001128164.2:c.624_626dupGCA

Variant names:

• chr6-16327684-A-ATGC
• rs193922926
• NM_001128164.2:c.624_626dupGCA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001128164.2(ATXN1):​c.624_626dupGCA​(p.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 0.15 (1525 hom., cov: 20)
  • Exomes 𝑓: 0.10 (4563 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN1 NM_001128164.2 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001128164.2
• BP6: Variant 6-16327684-A-ATGC is Benign according to our data. Variant chr6-16327684-A-ATGC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 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.624_626dupGCA	p.Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.624_626dupGCA	p.Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.*37_*39dupGCA		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.624_626dupGCA	p.Gln208dup	disruptive_inframe_insertion	Exon 7 of 8	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.624_626dupGCA	p.Gln208dup	disruptive_inframe_insertion	Exon 8 of 9	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000642969.1		c.*37_*39dupGCA		downstream_gene	N/A	ENSP00000493530.1	A0A2R8YCF3

Frequencies

GnomAD3 genomes AF: 0.151 AC: 20197 AN: 133820 Hom.: 1522 Cov.: 20

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0597

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0860

Gnomad MID AF: 0.176

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.157

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.101 AC: 129320 AN: 1276998 Hom.: 4563 Cov.: 32 AF XY: 0.102 AC XY: 64526 AN XY: 634658

African (AFR) AF: 0.198 AC: 5028 AN: 25410

American (AMR) AF: 0.141 AC: 4816 AN: 34164

Ashkenazi Jewish (ASJ) AF: 0.0887 AC: 2136 AN: 24080

East Asian (EAS) AF: 0.0644 AC: 1948 AN: 30228

South Asian (SAS) AF: 0.111 AC: 7816 AN: 70102

European-Finnish (FIN) AF: 0.0861 AC: 3419 AN: 39724

Middle Eastern (MID) AF: 0.115 AC: 507 AN: 4404

European-Non Finnish (NFE) AF: 0.0986 AC: 98206 AN: 996118

Other (OTH) AF: 0.103 AC: 5444 AN: 52768

GnomAD4 genome AF: 0.151 AC: 20219 AN: 133914 Hom.: 1525 Cov.: 20 AF XY: 0.148 AC XY: 9662 AN XY: 65072

African (AFR) AF: 0.240 AC: 7837 AN: 32678

American (AMR) AF: 0.149 AC: 1974 AN: 13230

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 356 AN: 3272

East Asian (EAS) AF: 0.0596 AC: 240 AN: 4024

South Asian (SAS) AF: 0.113 AC: 444 AN: 3918

European-Finnish (FIN) AF: 0.0860 AC: 837 AN: 9734

Middle Eastern (MID) AF: 0.187 AC: 47 AN: 252

European-Non Finnish (NFE) AF: 0.127 AC: 8120 AN: 64136

Other (OTH) AF: 0.155 AC: 281 AN: 1810

Alfa AF: 0.0694 Hom.: 48

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	ATXN1-related disorder (1)
-	-	1	Spinocerebellar ataxia type 1 (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: COSV55211707; COSMIC: COSV55211707;