rs2737699

Positions:

chr13-23331572-A-G

Variant summary

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

The NM_014363.6(SACS):c.12304T>C(p.Leu4102Leu) 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 1,613,452 control chromosomes in the GnomAD database, including 58,017 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 ( 4550 hom., cov: 33)

Exomes 𝑓: 0.27 ( 53467 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.23

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:

SACS (HGNC:):

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=-0.83).

BP6

Variant 13-23331572-A-G is Benign according to our data. Variant chr13-23331572-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 130201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23331572-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.23 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.34 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.12304T>C	p.Leu4102Leu	synonymous_variant	10/10	ENST00000382292.9	NP_055178.3	Q9NZJ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 linkuse as main transcript	c.12304T>C	p.Leu4102Leu	synonymous_variant	10/10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34363

AN:

152046

Hom.:

4547

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0911

Gnomad AMI

AF:

0.167

Gnomad AMR

AF:

0.325

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.340

Gnomad SAS

AF:

0.355

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.257

Gnomad OTH

AF:

0.255

GnomAD3 exomes

AF:

0.287

AC:

71855

AN:

250566

Hom.:

11122

AF XY:

0.288

AC XY:

38978

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.0882

Gnomad AMR exome

AF:

0.388

Gnomad ASJ exome

AF:

0.402

Gnomad EAS exome

AF:

0.351

Gnomad SAS exome

AF:

0.342

Gnomad FIN exome

AF:

0.245

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.278

GnomAD4 exome

AF:

0.266

AC:

388486

AN:

1461286

Hom.:

53467

Cov.:

AF XY:

0.268

AC XY:

195052

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.0851

Gnomad4 AMR exome

AF:

0.378

Gnomad4 ASJ exome

AF:

0.402

Gnomad4 EAS exome

AF:

0.346

Gnomad4 SAS exome

AF:

0.341

Gnomad4 FIN exome

AF:

0.238

Gnomad4 NFE exome

AF:

0.256

Gnomad4 OTH exome

AF:

0.261

GnomAD4 genome

AF:

0.226

AC:

34378

AN:

152166

Hom.:

4550

Cov.:

AF XY:

0.231

AC XY:

17197

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0911

Gnomad4 AMR

AF:

0.325

Gnomad4 ASJ

AF:

0.401

Gnomad4 EAS

AF:

0.340

Gnomad4 SAS

AF:

0.354

Gnomad4 FIN

AF:

0.235

Gnomad4 NFE

AF:

0.257

Gnomad4 OTH

AF:

0.258

Alfa

AF:

0.264

Hom.:

11449

Bravo

AF:

0.229

Asia WGS

AF:

0.317

AC:

1103

AN:

3478

EpiCase

AF:

0.264

EpiControl

AF:

0.268

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

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

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.	Nov 19, 2019	- -
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

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.6

DANN

Benign

0.34

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