rs1536365

Positions:

• chr13-23354956-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014363.6(SACS):​c.1656A>G​(p.Leu552=) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L552L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.088 (784 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10469 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.212

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]

ACMG classification

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	UniProt
SACS	NM_014363.6	c.1656A>G	p.Leu552=	synonymous_variant	8/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.1656A>G	p.Leu552=	synonymous_variant	8/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.0886 AC: 13478 AN: 152192 Hom.: 783 Cov.: 33

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

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.: 34 AF XY: 0.117 AC XY: 85027 AN XY: 727218

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.: 33 AF XY: 0.0902 AC XY: 6721 AN XY: 74474

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

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

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

Other links and lift over

dbSNP: rs1536365; hg19: chr13-23929095; COSMIC: COSV66536720; COSMIC: COSV66536720;