rs201030692

chr6-16327690-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 13/19 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.06

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 -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 GnomAd at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN1	NM_001128164.2	c.621G>T	p.Gln207His	missense_variant	7/8	ENST00000436367.6
ATXN1	NM_000332.4	c.621G>T	p.Gln207His	missense_variant	8/9
ATXN1	NM_001357857.2	c.*34G>T		3_prime_UTR_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN1	ENST00000436367.6	c.621G>T	p.Gln207His	missense_variant	7/8	1	NM_001128164.2	P1
ATXN1	ENST00000244769.8	c.621G>T	p.Gln207His	missense_variant	8/9	1		P1
ATXN1	ENST00000642969.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.000570 AC: 79 AN: 138632 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000546 AC XY: 50 AN XY: 91580

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.: 1 Cov.: 35 AF XY: 0.000338 AC XY: 213 AN XY: 630484

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: 79 AN: 138710 Hom.: 0 Cov.: 32 AF XY: 0.000518 AC XY: 35 AN XY: 67622

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.: 0

ExAC AF: 0.00307 AC: 332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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	T
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	N
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.49	T
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	T
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

Other links and lift over

dbSNP: rs201030692; hg19: chr6-16327921; COSMIC: COSV55208738; COSMIC: COSV55208738;