rs17078601

Positions:

chr13-23332844-G-C

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 260391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23332844-G-C is described in Lovd as [Benign]. Variant chr13-23332844-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACS	NM_014363.6 linkuse as main transcript	c.11032C>G	p.Pro3678Ala	missense_variant	10/10	ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 linkuse as main transcript	c.11032C>G	p.Pro3678Ala	missense_variant	10/10	5	NM_014363.6	ENSP00000371729	P1	Q9NZJ4-1

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

GnomAD3 exomes

AF:

0.0405

AC:

10148

AN:

250504

Hom.:

304

AF XY:

0.0404

AC XY:

5472

AN XY:

135426

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 SAS exome

AF:

0.0590

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

Gnomad4 AFR exome

AF:

0.00311

Gnomad4 AMR exome

AF:

0.0450

Gnomad4 ASJ exome

AF:

0.00861

Gnomad4 EAS exome

AF:

0.125

Gnomad4 SAS exome

AF:

0.0576

Gnomad4 FIN exome

AF:

0.0848

Gnomad4 NFE exome

AF:

0.0206

Gnomad4 OTH exome

AF:

0.0297

GnomAD4 genome

AF:

0.0266

AC:

4049

AN:

152316

Hom.:

105

Cov.:

AF XY:

0.0303

AC XY:

2259

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00402

Gnomad4 AMR

AF:

0.0295

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.116

Gnomad4 SAS

AF:

0.0579

Gnomad4 FIN

AF:

0.0904

Gnomad4 NFE

AF:

0.0223

Gnomad4 OTH

AF:

0.0218

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Charlevoix-Saguenay spastic ataxia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.6

.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.81

N;N

REVEL

Uncertain

0.37

Sift

Benign

0.033

D;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.59

ClinPred

0.039

GERP RS

5.8

Varity_R

0.094

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over