rs2737699

chr13-23331572-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.12304T>C(p.Leu4102=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.23

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=-0.83).
• 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	UniProt
SACS	NM_014363.6	c.12304T>C	p.Leu4102=	synonymous_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.12304T>C	p.Leu4102=	synonymous_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34363 AN: 152046 Hom.: 4547 Cov.: 33

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

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.: 36 AF XY: 0.268 AC XY: 195052 AN XY: 726978

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.: 33 AF XY: 0.231 AC XY: 17197 AN XY: 74388

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

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	- -

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 17, 2018	- -

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	-0.83
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

Other links and lift over

dbSNP: rs2737699; hg19: chr13-23905711; COSMIC: COSV66541037;