Genetic Variant ATXN1:p.Gln204_Gln208del (chr6-16327684-ATGCTGCTGCTGCTGC-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_001128164.2(ATXN1):c.612_626delGCAGCAGCAGCAGCA(p.Gln204_Gln208del) variant causes a disruptive inframe deletion 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATXN1
NM_001128164.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.123

Publications

0 publications found

Variant links:

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, Orphanet, Labcorp Genetics (formerly Invitae)

ATXN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001128164.2

BS2

High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ATXN1	NM_001128164.2 link	c.612_626delGCAGCAGCAGCAGCA	p.Gln204_Gln208del	disruptive_inframe_deletion	Exon 7 of 8	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4 link	c.612_626delGCAGCAGCAGCAGCA	p.Gln204_Gln208del	disruptive_inframe_deletion	Exon 8 of 9		NP_000323.2
ATXN1	NM_001357857.2 link	c.25_39delGCAGCAGCAGCAGCA		3_prime_UTR_variant	Exon 8 of 9		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ATXN1	ENST00000436367.6 link	c.612_626delGCAGCAGCAGCAGCA	p.Gln204_Gln208del	disruptive_inframe_deletion	Exon 7 of 8	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8 link	c.612_626delGCAGCAGCAGCAGCA	p.Gln204_Gln208del	disruptive_inframe_deletion	Exon 8 of 9	1		ENSP00000244769.3
ATXN1	ENST00000642969.1 link	c.25_39delGCAGCAGCAGCAGCA		downstream_gene_variant				ENSP00000493530.1

Frequencies

GnomAD3 genomes

AF:

0.000758

AC:

102

AN:

134640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000752

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000929

Gnomad OTH

AF:

0.00220

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000116

AC:

156

AN:

1339314

Hom.:

AF XY:

0.000113

AC XY:

AN XY:

665414

show subpopulations

African (AFR)

AF:

0.00264

AC:

AN:

26520

American (AMR)

AF:

0.000141

AC:

AN:

35506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24870

East Asian (EAS)

AF:

0.0000327

AC:

AN:

30604

South Asian (SAS)

AF:

0.000107

AC:

AN:

74452

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40208

Middle Eastern (MID)

AF:

0.000217

AC:

AN:

4600

European-Non Finnish (NFE)

AF:

0.0000516

AC:

AN:

1047488

Other (OTH)

AF:

0.000309

AC:

AN:

55066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000764

AC:

103

AN:

134738

Hom.:

Cov.:

AF XY:

0.000611

AC XY:

AN XY:

65508

show subpopulations

African (AFR)

AF:

0.00277

AC:

AN:

32834

American (AMR)

AF:

0.0000751

AC:

AN:

13314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3278

East Asian (EAS)

AF:

0.00

AC:

AN:

4028

South Asian (SAS)

AF:

0.000253

AC:

AN:

3956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.0000929

AC:

AN:

64556

Other (OTH)

AF:

0.00218

AC:

AN:

1834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.12

Mutation Taster

=192/8

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over