rs201030692

Positions:

chr6-16327690-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001128164.2(ATXN1):c.621G>T(p.Gln207His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000363 in 1,409,294 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

ATXN1
NM_001128164.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -2.06

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032785237).

BP6

Variant 6-16327690-C-A is Benign according to our data. Variant chr6-16327690-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210502.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN1	NM_001128164.2 linkuse as main transcript	c.621G>T	p.Gln207His	missense_variant	7/8	ENST00000436367.6	NP_001121636.1	P54253-1Q96FF1
ATXN1	NM_000332.4 linkuse as main transcript	c.621G>T	p.Gln207His	missense_variant	8/9		NP_000323.2	P54253-1Q96FF1
ATXN1	NM_001357857.2 linkuse as main transcript	c.*34G>T		3_prime_UTR_variant	8/9		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ATXN1	ENST00000436367.6 linkuse as main transcript	c.621G>T	p.Gln207His	missense_variant	7/8	1	NM_001128164.2	ENSP00000416360.1	P54253-1
ATXN1	ENST00000244769.8 linkuse as main transcript	c.621G>T	p.Gln207His	missense_variant	8/9	1		ENSP00000244769.3	P54253-1
ATXN1	ENST00000642969.1 linkuse as main transcript	c.*34G>T		downstream_gene_variant				ENSP00000493530.1	A0A2R8YCF3

Frequencies

GnomAD3 genomes

AF:

0.000570

AC:

AN:

138632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000907

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000210

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000534

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000642

AC:

106

AN:

165226

Hom.:

AF XY:

0.000546

AC XY:

AN XY:

91580

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.000542

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000831

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.000674

Gnomad NFE exome

AF:

0.000794

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.000340

AC:

432

AN:

1270584

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

213

AN XY:

630484

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000569

Gnomad4 ASJ exome

AF:

0.0000409

Gnomad4 EAS exome

AF:

0.00121

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.000735

Gnomad4 NFE exome

AF:

0.000266

Gnomad4 OTH exome

AF:

0.000501

GnomAD4 genome

AF:

0.000570

AC:

AN:

138710

Hom.:

Cov.:

AF XY:

0.000518

AC XY:

AN XY:

67622

show subpopulations

Gnomad4 AFR

AF:

0.000905

Gnomad4 AMR

AF:

0.000222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000202

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.000210

Gnomad4 NFE

AF:

0.000534

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0174

Hom.:

ExAC

AF:

0.00307

AC:

332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 27, 2014

- -

Spinocerebellar ataxia type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.55

DANN

Benign

0.49

DEOGEN2

Benign

0.28

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.24

.;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.27

N;N

REVEL

Benign

0.14

Sift

Benign

0.10

T;T

Sift4G

Uncertain

0.015

D;D

Polyphen

0.97

D;D

Vest4

0.12

MutPred

0.20

Loss of solvent accessibility (P = 0.4653);Loss of solvent accessibility (P = 0.4653);

MVP

0.60

MPC

0.39

ClinPred

0.016

GERP RS

-0.093

Varity_R

0.10

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over