rs9550956

chr13-23337609-C-T

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.6267G>A(p.Ser2089=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,724 control chromosomes in the GnomAD database, including 2,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (224 hom., cov: 33)
  • Exomes 𝑓: 0.014 (1870 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.240

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=-0.78).
• BP6: Variant 13-23337609-C-T is Benign according to our data. Variant chr13-23337609-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 283782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23337609-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.6267G>A	p.Ser2089=	synonymous_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.6267G>A	p.Ser2089=	synonymous_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2042 AN: 152016 Hom.: 225 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0319 AC: 7991 AN: 250214 Hom.: 772 AF XY: 0.0347 AC XY: 4688 AN XY: 135294

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.250

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000399

Gnomad OTH exome AF: 0.0164

GnomAD4 exome AF: 0.0139 AC: 20298 AN: 1461590 Hom.: 1870 Cov.: 37 AF XY: 0.0162 AC XY: 11780 AN XY: 727070

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.0985

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000299

Gnomad4 OTH exome AF: 0.0268

GnomAD4 genome AF: 0.0134 AC: 2039 AN: 152134 Hom.: 224 Cov.: 33 AF XY: 0.0162 AC XY: 1207 AN XY: 74364

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00151 Hom.: 8

Bravo AF: 0.0112

Asia WGS AF: 0.175 AC: 607 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 13, 2015	- -
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:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2018	- -

Charlevoix-Saguenay spastic ataxia Benign:2

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	2.9
Dann	Benign	0.48

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: rs9550956; hg19: chr13-23911748; COSMIC: COSV66536697;