rs4143768

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014363.6(SACS):c.6195T>C(p.Ile2065=) 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

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 -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 [Likely_benign]. Clinvar id is 130203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23337681-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
SACS	NM_014363.6 linkuse as main transcript	c.6195T>C	p.Ile2065=	synonymous_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.6195T>C	p.Ile2065=	synonymous_variant	10/10	5	NM_014363.6	ENSP00000371729	P1	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

GnomAD3 exomes

AF:

0.288

AC:

71541

AN:

248368

Hom.:

11078

AF XY:

0.288

AC XY:

38874

AN XY:

134808

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 SAS exome

AF:

0.344

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

Gnomad4 AFR exome

AF:

0.0853

Gnomad4 AMR exome

AF:

0.379

Gnomad4 ASJ exome

AF:

0.402

Gnomad4 EAS exome

AF:

0.346

Gnomad4 SAS exome

AF:

0.342

Gnomad4 FIN exome

AF:

0.239

Gnomad4 NFE exome

AF:

0.257

Gnomad4 OTH exome

AF:

0.261

GnomAD4 genome

AF:

0.226

AC:

34437

AN:

152068

Hom.:

4574

Cov.:

AF XY:

0.232

AC XY:

17237

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0914

Gnomad4 AMR

AF:

0.327

Gnomad4 ASJ

AF:

0.402

Gnomad4 EAS

AF:

0.340

Gnomad4 SAS

AF:

0.355

Gnomad4 FIN

AF:

0.237

Gnomad4 NFE

AF:

0.258

Gnomad4 OTH

AF:

0.258

Alfa

AF:

0.270

Hom.:

6237

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

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 21, 2019	- -

Charlevoix-Saguenay spastic ataxia

Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

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

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.2

DANN

Benign

0.67

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