chr6-16306520-G-A

Variant names:

• chr6-16306520-G-A
• rs16885
• NM_001128164.2:c.2257C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001128164.2(ATXN1):​c.2257C>T​(p.Pro753Ser) variant causes a missense change. The variant allele was found at a frequency of 0.187 in 1,614,034 control chromosomes in the GnomAD database, including 30,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (2367 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28501 hom.)
• Consequence: ATXN1 NM_001128164.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.47
• Publications: 31 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012945831).
• BP6: Variant 6-16306520-G-A is Benign according to our data. Variant chr6-16306520-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128499.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN1	NM_001128164.2	c.2257C>T	p.Pro753Ser	missense_variant	Exon 8 of 8	ENST00000436367.6	NP_001121636.1
ATXN1	NM_000332.4	c.2257C>T	p.Pro753Ser	missense_variant	Exon 9 of 9		NP_000323.2
ATXN1	NM_001357857.2	c.*1670C>T		3_prime_UTR_variant	Exon 9 of 9		NP_001344786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN1	ENST00000436367.6	c.2257C>T	p.Pro753Ser	missense_variant	Exon 8 of 8	1	NM_001128164.2	ENSP00000416360.1
ATXN1	ENST00000244769.8	c.2257C>T	p.Pro753Ser	missense_variant	Exon 9 of 9	1		ENSP00000244769.3

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23559 AN: 152034 Hom.: 2367 Cov.: 32

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.00597

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.177

GnomAD2 exomes AF: 0.195 AC: 48925 AN: 251454 AF XY: 0.195

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.00843

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.190 AC: 278317 AN: 1461882 Hom.: 28501 Cov.: 33 AF XY: 0.191 AC XY: 139000 AN XY: 727244

African (AFR) AF: 0.0311 AC: 1041 AN: 33480

American (AMR) AF: 0.315 AC: 14109 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6584 AN: 26136

East Asian (EAS) AF: 0.00390 AC: 155 AN: 39700

South Asian (SAS) AF: 0.193 AC: 16615 AN: 86258

European-Finnish (FIN) AF: 0.189 AC: 10070 AN: 53414

Middle Eastern (MID) AF: 0.193 AC: 1111 AN: 5768

European-Non Finnish (NFE) AF: 0.196 AC: 218190 AN: 1112006

Other (OTH) AF: 0.173 AC: 10442 AN: 60396

GnomAD4 genome AF: 0.155 AC: 23564 AN: 152152 Hom.: 2367 Cov.: 32 AF XY: 0.158 AC XY: 11752 AN XY: 74374

African (AFR) AF: 0.0411 AC: 1708 AN: 41540

American (AMR) AF: 0.243 AC: 3708 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3470

East Asian (EAS) AF: 0.00579 AC: 30 AN: 5180

South Asian (SAS) AF: 0.198 AC: 954 AN: 4816

European-Finnish (FIN) AF: 0.198 AC: 2089 AN: 10576

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13412 AN: 67962

Other (OTH) AF: 0.175 AC: 370 AN: 2114

Alfa AF: 0.185 Hom.: 13302

Bravo AF: 0.154

TwinsUK AF: 0.195 AC: 723

ALSPAC AF: 0.200 AC: 771

ESP6500AA AF: 0.0413 AC: 182

ESP6500EA AF: 0.197 AC: 1693

ExAC AF: 0.189 AC: 22911

EpiCase AF: 0.205

EpiControl AF: 0.199

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	.;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.4	L;L
PhyloP100		4.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		0.29	B;B
Vest4		0.10
MPC		1.2
ClinPred		0.013	T
GERP RS		6.1
Varity_R		0.097
gMVP		0.19
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16885; hg19: chr6-16306751; COSMIC: COSV104392024;