chr13-23354956-T-C

Position:

chr13-23354956-T-C

Variant summary

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

The NM_014363.6(SACS):c.1656A>G(p.Leu552Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,152 control chromosomes in the GnomAD database, including 11,253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.088 ( 784 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10469 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.212

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=-0.66).

BP6

Variant 13-23354956-T-C is Benign according to our data. Variant chr13-23354956-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 130202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23354956-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.212 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.1656A>G	p.Leu552Leu	synonymous_variant	8/10	ENST00000382292.9	NP_055178.3	Q9NZJ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 link	c.1656A>G	p.Leu552Leu	synonymous_variant	8/10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.0886

AC:

13478

AN:

152192

Hom.:

783

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0786

Gnomad ASJ

AF:

0.0822

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.155

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.0957

GnomAD3 exomes

AF:

0.112

AC:

28125

AN:

251274

Hom.:

1763

AF XY:

0.116

AC XY:

15690

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.0177

Gnomad AMR exome

AF:

0.0826

Gnomad ASJ exome

AF:

0.0807

Gnomad EAS exome

AF:

0.115

Gnomad SAS exome

AF:

0.132

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.115

GnomAD4 exome

AF:

0.116

AC:

169589

AN:

1461842

Hom.:

10469

Cov.:

AF XY:

0.117

AC XY:

85027

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0174

Gnomad4 AMR exome

AF:

0.0814

Gnomad4 ASJ exome

AF:

0.0806

Gnomad4 EAS exome

AF:

0.135

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.163

Gnomad4 NFE exome

AF:

0.118

Gnomad4 OTH exome

AF:

0.110

GnomAD4 genome

AF:

0.0885

AC:

13479

AN:

152310

Hom.:

784

Cov.:

AF XY:

0.0902

AC XY:

6721

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0201

Gnomad4 AMR

AF:

0.0785

Gnomad4 ASJ

AF:

0.0822

Gnomad4 EAS

AF:

0.127

Gnomad4 SAS

AF:

0.130

Gnomad4 FIN

AF:

0.155

Gnomad4 NFE

AF:

0.117

Gnomad4 OTH

AF:

0.0942

Alfa

AF:

0.107

Hom.:

1314

Bravo

AF:

0.0796

Asia WGS

AF:

0.113

AC:

392

AN:

3478

EpiCase

AF:

0.112

EpiControl

AF:

0.113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

-0.66

CADD

Benign

8.0

DANN

Benign

0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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