13-23335023-A-G

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.8853T>C(p.Val2951=) 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 1,613,350 control chromosomes in the GnomAD database, including 58,049 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. V2951V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.23 (4559 hom., cov: 33)
  • Exomes 𝑓: 0.27 (53490 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.156

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=-0.72).
• BP6: Variant 13-23335023-A-G is Benign according to our data. Variant chr13-23335023-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 130205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23335023-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.156 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	UniProt
SACS	NM_014363.6	c.8853T>C	p.Val2951=	synonymous_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.8853T>C	p.Val2951=	synonymous_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34398 AN: 152080 Hom.: 4556 Cov.: 33

Gnomad AFR AF: 0.0914

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.256

GnomAD3 exomes AF: 0.287 AC: 71940 AN: 250780 Hom.: 11138 AF XY: 0.288 AC XY: 39005 AN XY: 135532

Gnomad AFR exome AF: 0.0885

Gnomad AMR exome AF: 0.388

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.350

Gnomad SAS exome AF: 0.343

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.266 AC: 388691 AN: 1461152 Hom.: 53490 Cov.: 40 AF XY: 0.268 AC XY: 195147 AN XY: 726852

Gnomad4 AFR exome AF: 0.0856

Gnomad4 AMR exome AF: 0.378

Gnomad4 ASJ exome AF: 0.402

Gnomad4 EAS exome AF: 0.345

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.239

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.226 AC: 34413 AN: 152198 Hom.: 4559 Cov.: 33 AF XY: 0.231 AC XY: 17215 AN XY: 74422

Gnomad4 AFR AF: 0.0915

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.339

Gnomad4 SAS AF: 0.354

Gnomad4 FIN AF: 0.235

Gnomad4 NFE AF: 0.257

Gnomad4 OTH AF: 0.258

Alfa AF: 0.263 Hom.: 7446

Bravo AF: 0.230

Asia WGS AF: 0.317 AC: 1103 AN: 3478

EpiCase AF: 0.265

EpiControl AF: 0.268

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2014	- -
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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 04, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2017	Variant summary: The SACS c.8853T>C (p.Val2951Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp55. However, these predictions have yet to be confirmed by functional studies. This variant was found in 74944/252514 control chromosomes (127 homozygotes) at a frequency of 0.2967915, which is approximately 38 times the estimated maximal expected allele frequency of a pathogenic SACS variant (0.0079057), suggesting this variant is likely a benign polymorphism. This variant has been reported in a validation study with high allele frequency and was classified as polymorphism by authors (Vermeer_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

Charlevoix-Saguenay spastic ataxia Benign:3

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.	Sep 16, 2020	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	This variant is associated with the following publications: (PMID: 19779133) -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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	-0.72
Cadd	Benign	0.45
Dann	Benign	0.62

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: rs9552929; hg19: chr13-23909162; COSMIC: COSV104428861;