NM_014363.6:c.11032C>G

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.11032C>G(p.Pro3678Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,613,774 control chromosomes in the GnomAD database, including 1,131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 105 hom., cov: 33)

Exomes 𝑓: 0.028 ( 1026 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 10.0

Publications

13 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=0.002728641).

BP6

Variant 13-23332844-G-C is Benign according to our data. Variant chr13-23332844-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 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.11032C>G	p.Pro3678Ala	missense	Exon 10 of 10	NP_055178.3
SACS	NM_001437336.1		c.11059C>G	p.Pro3687Ala	missense	Exon 11 of 11	NP_001424265.1
SACS	NM_001278055.2		c.10591C>G	p.Pro3531Ala	missense	Exon 8 of 8	NP_001264984.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SACS	ENST00000382292.9	TSL:5 MANE Select	c.11032C>G	p.Pro3678Ala	missense	Exon 10 of 10	ENSP00000371729.3
SACS	ENST00000455470.6	TSL:1	c.2432-3360C>G		intron	N/A	ENSP00000406565.2
SACS	ENST00000682944.1		c.11059C>G	p.Pro3687Ala	missense	Exon 11 of 11	ENSP00000507173.1

Frequencies

GnomAD3 genomes

AF:

0.0266

AC:

4051

AN:

152198

Hom.:

106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0296

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.0577

Gnomad FIN

AF:

0.0904

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0223

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0405

AC:

10148

AN:

250504

AF XY:

0.0404

show subpopulations

Gnomad AFR exome

AF:

0.00370

Gnomad AMR exome

AF:

0.0484

Gnomad ASJ exome

AF:

0.00964

Gnomad EAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.0860

Gnomad NFE exome

AF:

0.0227

Gnomad OTH exome

AF:

0.0306

GnomAD4 exome

AF:

0.0285

AC:

41590

AN:

1461458

Hom.:

1026

Cov.:

AF XY:

0.0292

AC XY:

21266

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33470

American (AMR)

AF:

0.0450

AC:

2013

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00861

AC:

225

AN:

26128

East Asian (EAS)

AF:

0.125

AC:

4975

AN:

39690

South Asian (SAS)

AF:

0.0576

AC:

4966

AN:

86248

European-Finnish (FIN)

AF:

0.0848

AC:

4509

AN:

53146

Middle Eastern (MID)

AF:

0.0151

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0206

AC:

22919

AN:

1111894

Other (OTH)

AF:

0.0297

AC:

1792

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2551

5102

7653

10204

12755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

926

1852

2778

3704

4630

<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:

0.0266

AC:

4049

AN:

152316

Hom.:

105

Cov.:

AF XY:

0.0303

AC XY:

2259

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00402

AC:

167

AN:

41588

American (AMR)

AF:

0.0295

AC:

452

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.116

AC:

599

AN:

5182

South Asian (SAS)

AF:

0.0579

AC:

280

AN:

4832

European-Finnish (FIN)

AF:

0.0904

AC:

959

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0223

AC:

1516

AN:

68016

Other (OTH)

AF:

0.0218

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

210

420

631

841

1051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0241

Hom.:

Bravo

AF:

0.0215

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0195

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0229

AC:

197

ExAC

AF:

0.0396

AC:

4807

Asia WGS

AF:

0.0660

AC:

228

AN:

3478

EpiCase

AF:

0.0196

EpiControl

AF:

0.0196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 22, 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

not specified

Benign:3

Dec 12, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

Charlevoix-Saguenay spastic ataxia

Benign:3

Jul 01, 2021

Genome-Nilou Lab

Significance: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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Spastic paraplegia

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spastic paraplegia

Benign:1

Aug 30, 2021

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

0.22

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.6

PhyloP100

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.81

REVEL

Uncertain

0.37

Sift

Benign

0.033

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.59

ClinPred

0.039

GERP RS

5.8

Varity_R

0.094

gMVP

0.63

Mutation Taster

=88/12

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