rs4143768

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014363.6(SACS):c.6195T>C(p.Ile2065Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,612,498 control chromosomes in the GnomAD database, including 58,136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4574 hom., cov: 32)

Exomes 𝑓: 0.27 ( 53562 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.32

Publications

18 publications found

Variant links:

Genes affected

SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

SACS Gene-Disease associations (from GenCC):

Charlevoix-Saguenay spastic ataxia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

SACS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 13-23337681-A-G is Benign according to our data. Variant chr13-23337681-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.6195T>C	p.Ile2065Ile	synonymous_variant	Exon 10 of 10	ENST00000382292.9	NP_055178.3	Q9NZJ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 link	c.6195T>C	p.Ile2065Ile	synonymous_variant	Exon 10 of 10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34421

AN:

151948

Hom.:

4571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0913

Gnomad AMI

AF:

0.167

Gnomad AMR

AF:

0.326

Gnomad ASJ

AF:

0.402

Gnomad EAS

AF:

0.340

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.237

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.258

Gnomad OTH

AF:

0.256

GnomAD2 exomes

AF:

0.288

AC:

71541

AN:

248368

AF XY:

0.288

show subpopulations

Gnomad AFR exome

AF:

0.0885

Gnomad AMR exome

AF:

0.388

Gnomad ASJ exome

AF:

0.402

Gnomad EAS exome

AF:

0.352

Gnomad FIN exome

AF:

0.246

Gnomad NFE exome

AF:

0.258

Gnomad OTH exome

AF:

0.279

GnomAD4 exome

AF:

0.266

AC:

388829

AN:

1460430

Hom.:

53562

Cov.:

AF XY:

0.269

AC XY:

195190

AN XY:

726486

show subpopulations

African (AFR)

AF:

0.0853

AC:

2845

AN:

33350

American (AMR)

AF:

0.379

AC:

16875

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.402

AC:

10487

AN:

26108

East Asian (EAS)

AF:

0.346

AC:

13736

AN:

39682

South Asian (SAS)

AF:

0.342

AC:

29363

AN:

85970

European-Finnish (FIN)

AF:

0.239

AC:

12722

AN:

53156

Middle Eastern (MID)

AF:

0.326

AC:

1880

AN:

5766

European-Non Finnish (NFE)

AF:

0.257

AC:

285157

AN:

1111524

Other (OTH)

AF:

0.261

AC:

15764

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

16805

33611

50416

67222

84027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9812

19624

29436

39248

49060

<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:

0.226

AC:

34437

AN:

152068

Hom.:

4574

Cov.:

AF XY:

0.232

AC XY:

17237

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0914

AC:

3793

AN:

41514

American (AMR)

AF:

0.327

AC:

4987

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.402

AC:

1392

AN:

3464

East Asian (EAS)

AF:

0.340

AC:

1755

AN:

5164

South Asian (SAS)

AF:

0.355

AC:

1707

AN:

4812

European-Finnish (FIN)

AF:

0.237

AC:

2500

AN:

10568

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.258

AC:

17516

AN:

67956

Other (OTH)

AF:

0.258

AC:

546

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1321

2643

3964

5286

6607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<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:

0.257

Hom.:

14222

Bravo

AF:

0.230

Asia WGS

AF:

0.318

AC:

1107

AN:

3478

EpiCase

AF:

0.265

EpiControl

AF:

0.268

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

not provided

Benign:4

May 21, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charlevoix-Saguenay spastic ataxia

Benign:3

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.2

(source)

DANN

Benign

0.67

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over