6-16306627-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001128164.2(ATXN1):c.2150C>T(p.Ala717Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,614,222 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (25 hom.)
• Consequence: ATXN1 NM_001128164.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.10

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049659014).
• BP6: Variant 6-16306627-G-A is Benign according to our data. Variant chr6-16306627-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 522259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-16306627-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 434 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.2150C>T	p.Ala717Val	missense_variant	8/8	ENST00000436367.6
ATXN1	NM_000332.4	c.2150C>T	p.Ala717Val	missense_variant	9/9
ATXN1	NM_001357857.2	c.*1563C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.2150C>T	p.Ala717Val	missense_variant	8/8	1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.2150C>T	p.Ala717Val	missense_variant	9/9	1		P1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152214 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00470

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00274 AC: 688 AN: 251400 Hom.: 0 AF XY: 0.00285 AC XY: 387 AN XY: 135870

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00446 AC: 6526 AN: 1461890 Hom.: 25 Cov.: 31 AF XY: 0.00436 AC XY: 3170 AN XY: 727244

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00201

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.00525

Gnomad4 OTH exome AF: 0.00439

GnomAD4 genome AF: 0.00285 AC: 434 AN: 152332 Hom.: 3 Cov.: 33 AF XY: 0.00262 AC XY: 195 AN XY: 74494

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00470

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00389 Hom.: 3

Bravo AF: 0.00285

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00246 AC: 299

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00397

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 31, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Oct 30, 2017

BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.28	N
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.11
Sift	Benign	0.28	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.010	B;B
Vest4		0.042
MVP		0.74
MPC		0.41
ClinPred		0.0079	T
GERP RS		2.9
Varity_R		0.048
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs41267702; hg19: chr6-16306858; COSMIC: COSV104392072;