rs17078608

chr13-23336727-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014363.6(SACS):c.7149C>T(p.Arg2383=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 1,613,684 control chromosomes in the GnomAD database, including 92 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 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (65 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.862

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 13-23336727-G-A is Benign according to our data. Variant chr13-23336727-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 458273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23336727-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.862 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1992/152112) while in subpopulation AFR AF= 0.0298 (1236/41466). AF 95% confidence interval is 0.0284. There are 27 homozygotes in gnomad4. There are 1050 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.7149C>T	p.Arg2383=	synonymous_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.7149C>T	p.Arg2383=	synonymous_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1984 AN: 151994 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00321

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.00724 AC: 1813 AN: 250430 Hom.: 27 AF XY: 0.00678 AC XY: 919 AN XY: 135586

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.0350

Gnomad NFE exome AF: 0.00336

Gnomad OTH exome AF: 0.00362

GnomAD4 exome AF: 0.00407 AC: 5954 AN: 1461572 Hom.: 65 Cov.: 37 AF XY: 0.00393 AC XY: 2858 AN XY: 727094

Gnomad4 AFR exome AF: 0.0343

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.000857

Gnomad4 SAS exome AF: 0.00176

Gnomad4 FIN exome AF: 0.0320

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00449

GnomAD4 genome AF: 0.0131 AC: 1992 AN: 152112 Hom.: 27 Cov.: 33 AF XY: 0.0141 AC XY: 1050 AN XY: 74378

Gnomad4 AFR AF: 0.0298

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0389

Gnomad4 NFE AF: 0.00321

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.00645 Hom.: 10

Bravo AF: 0.0112

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2020	- -

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	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 24, 2020

- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	8.3
Dann	Benign	0.41

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: rs17078608; hg19: chr13-23910866; COSMIC: COSV66538758;