rs186436335

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_014363.6(SACS):c.8245A>G(p.Ile2749Val) variant causes a missense change. The variant allele was found at a frequency of 0.000281 in 1,613,960 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 4.77

Publications

4 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058905184).

BP6

Variant 13-23335631-T-C is Benign according to our data. Variant chr13-23335631-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 411694.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.8245A>G	p.Ile2749Val	missense_variant	Exon 10 of 10	ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 link	c.8245A>G	p.Ile2749Val	missense_variant	Exon 10 of 10	5	NM_014363.6	ENSP00000371729.3

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000267

AC:

AN:

250838

AF XY:

0.000288

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.000397

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000294

AC:

430

AN:

1461668

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

244

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000301

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000342

AC:

380

AN:

1111886

Other (OTH)

AF:

0.000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000151

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68000

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000298

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jul 28, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Nov 10, 2023

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SACS c.8245A>G (p.Ile2749Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 1613960 control chromosomes in the gnomAD database, including 1 homozygotes (gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (0.00028 vs 0.0079), allowing no conclusion about variant significance. c.8245A>G has been reported in the literature in individuals affected with Ataxia (Ngo_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31692161). ClinVar contains an entry for this variant (Variation ID: 411694). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary spastic paraplegia

Uncertain:1

Feb 12, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability

Uncertain:1

Nov 28, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charlevoix-Saguenay spastic ataxia

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.086

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.059

T;T

MetaSVM

Uncertain

0.064

MutationAssessor

Benign

1.6

.;L

PhyloP100

4.8

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.68

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.16

T;T

Sift4G

Uncertain

0.052

T;D

Polyphen

0.15

.;B

Vest4

0.25

MVP

0.74

ClinPred

0.025

GERP RS

5.3

Varity_R

0.14

gMVP

0.25

Mutation Taster

=52/48

polymorphism

(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