NM_001128164.2:c.636G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001128164.2(ATXN1):c.636G>T(p.Gln212His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000495 in 1,515,692 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q212P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

ATXN1
NM_001128164.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.00

Publications

6 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0496521).

BS2

High AC in GnomAd4 at 11 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATXN1	NM_001128164.2	MANE Select	c.636G>T	p.Gln212His	missense	Exon 7 of 8	NP_001121636.1
ATXN1	NM_000332.4		c.636G>T	p.Gln212His	missense	Exon 8 of 9	NP_000323.2
ATXN1	NM_001357857.2		c.*49G>T		3_prime_UTR	Exon 8 of 9	NP_001344786.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATXN1	ENST00000436367.6	TSL:1 MANE Select	c.636G>T	p.Gln212His	missense	Exon 7 of 8	ENSP00000416360.1
ATXN1	ENST00000244769.8	TSL:1	c.636G>T	p.Gln212His	missense	Exon 8 of 9	ENSP00000244769.3
ATXN1	ENST00000642969.1		c.*49G>T		downstream_gene	N/A	ENSP00000493530.1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

119624

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000844

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:

0.0000487

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000631

AC:

AN:

142684

AF XY:

0.0000630

show subpopulations

Gnomad AFR exome

AF:

0.000317

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000305

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1395978

Hom.:

Cov.:

120

AF XY:

0.0000403

AC XY:

AN XY:

694028

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

26682

American (AMR)

AF:

0.0000500

AC:

AN:

39964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25340

East Asian (EAS)

AF:

0.0000573

AC:

AN:

34908

South Asian (SAS)

AF:

0.0000368

AC:

AN:

81508

European-Finnish (FIN)

AF:

0.0000917

AC:

AN:

43600

Middle Eastern (MID)

AF:

0.000193

AC:

AN:

5176

European-Non Finnish (NFE)

AF:

0.0000444

AC:

AN:

1081554

Other (OTH)

AF:

0.00

AC:

AN:

57246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

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:

0.0000919

AC:

AN:

119714

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

58180

show subpopulations

African (AFR)

AF:

0.000279

AC:

AN:

25132

American (AMR)

AF:

0.0000843

AC:

AN:

11868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3152

East Asian (EAS)

AF:

0.00

AC:

AN:

2316

South Asian (SAS)

AF:

0.00

AC:

AN:

3508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.0000487

AC:

AN:

61652

Other (OTH)

AF:

0.00

AC:

AN:

1692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.00927

Hom.:

ExAC

AF:

0.0000305

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Spinocerebellar ataxia type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

9.0

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.32

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.19

M_CAP

Benign

0.066

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.25

REVEL

Benign

0.0090

Sift

Benign

0.10

Sift4G

Uncertain

0.0050

Vest4

0.18

MutPred

0.24

Loss of helix (P = 0.2271)

MVP

0.72

MPC

0.39

ClinPred

0.030

Varity_R

0.13

gMVP

0.41

Mutation Taster

=100/0

polymorphism

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over