13-23355916-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014363.6(SACS):c.696T>A(p.Asn232Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,054 control chromosomes in the GnomAD database, including 11,232 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N232N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.089 ( 780 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10452 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.354

Publications

26 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023277998).

BP6

Variant 13-23355916-A-T is Benign according to our data. Variant chr13-23355916-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014363.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SACS	NM_014363.6	MANE Select	c.696T>A	p.Asn232Lys	missense	Exon 8 of 10	NP_055178.3
SACS	NM_001437336.1		c.696T>A	p.Asn232Lys	missense	Exon 8 of 11	NP_001424265.1
SACS	NM_001278055.2		c.255T>A	p.Asn85Lys	missense	Exon 6 of 8	NP_001264984.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SACS	ENST00000382292.9	TSL:5 MANE Select	c.696T>A	p.Asn232Lys	missense	Exon 8 of 10	ENSP00000371729.3
SACS	ENST00000455470.6	TSL:1	c.696T>A	p.Asn232Lys	missense	Exon 8 of 11	ENSP00000406565.2
SACS	ENST00000682944.1		c.696T>A	p.Asn232Lys	missense	Exon 8 of 11	ENSP00000507173.1

Frequencies

GnomAD3 genomes

AF:

0.0887

AC:

13489

AN:

152136

Hom.:

779

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0201

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0785

Gnomad ASJ

AF:

0.0821

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.0962

GnomAD2 exomes

AF:

0.112

AC:

28085

AN:

251122

AF XY:

0.115

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.0823

Gnomad ASJ exome

AF:

0.0807

Gnomad EAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.116

AC:

169410

AN:

1461800

Hom.:

10452

Cov.:

AF XY:

0.117

AC XY:

84949

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.0174

AC:

581

AN:

33476

American (AMR)

AF:

0.0812

AC:

3630

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0806

AC:

2106

AN:

26134

East Asian (EAS)

AF:

0.134

AC:

5304

AN:

39696

South Asian (SAS)

AF:

0.130

AC:

11248

AN:

86256

European-Finnish (FIN)

AF:

0.163

AC:

8721

AN:

53402

Middle Eastern (MID)

AF:

0.102

AC:

590

AN:

5768

European-Non Finnish (NFE)

AF:

0.117

AC:

130564

AN:

1111954

Other (OTH)

AF:

0.110

AC:

6666

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

9292

18585

27877

37170

46462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4648

9296

13944

18592

23240

<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:

0.0886

AC:

13490

AN:

152254

Hom.:

780

Cov.:

AF XY:

0.0904

AC XY:

6732

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0201

AC:

834

AN:

41578

American (AMR)

AF:

0.0784

AC:

1199

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0821

AC:

285

AN:

3470

East Asian (EAS)

AF:

0.127

AC:

659

AN:

5178

South Asian (SAS)

AF:

0.129

AC:

623

AN:

4824

European-Finnish (FIN)

AF:

0.156

AC:

1655

AN:

10594

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8003

AN:

68002

Other (OTH)

AF:

0.0947

AC:

200

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

628

1256

1885

2513

3141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<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:

0.110

Hom.:

755

Bravo

AF:

0.0794

TwinsUK

AF:

0.117

AC:

435

ALSPAC

AF:

0.122

AC:

469

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.117

AC:

1002

ExAC

AF:

0.114

AC:

13834

Asia WGS

AF:

0.113

AC:

390

AN:

3478

EpiCase

AF:

0.112

EpiControl

AF:

0.113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia

Benign:5

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 21, 2015

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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.

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.078

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.35

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.31

Sift

Benign

0.21

Sift4G

Uncertain

0.0080

Polyphen

0.79

Vest4

0.29

MutPred

0.24

Gain of catalytic residue at W231 (P = 0)

ClinPred

0.040

GERP RS

0.71

Varity_R

0.31

gMVP

0.76

Mutation Taster

=261/39

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over