rs17078720

Variant names:

• chr13-23411252-T-C
• rs17078720
• NM_014363.6:c.-13A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-23411252-T-C
• chr13-23411252-T-A
• chr13-23411252-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014363.6(SACS):​c.-13A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,595,820 control chromosomes in the GnomAD database, including 85,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6804 hom., cov: 33)
  • Exomes 𝑓: 0.32 (78281 hom.)
• Consequence: SACS NM_014363.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.418
• Publications: 14 publications found

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]

SACS Gene-Disease associations (from GenCC):

• Charlevoix-Saguenay spastic ataxia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, PanelApp Australia, G2P, Myriad Women’s Health, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 13-23411252-T-C is Benign according to our data. Variant chr13-23411252-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014363.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	NM_014363.6	MANE Select	c.-13A>G		5_prime_UTR	Exon 2 of 10	NP_055178.3
	SACS	NM_001437336.1		c.-13A>G		5_prime_UTR	Exon 2 of 11	NP_001424265.1	A0A804HIQ1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.-13A>G		5_prime_UTR	Exon 2 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.-13A>G		5_prime_UTR	Exon 2 of 11	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682547.1		c.25A>G	p.Arg9Gly	missense	Exon 2 of 4	ENSP00000507735.1	A0A804HK18

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43515 AN: 151930 Hom.: 6799 Cov.: 33

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.310

GnomAD2 exomes AF: 0.327 AC: 81255 AN: 248422 AF XY: 0.335

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.324 AC: 468199 AN: 1443772 Hom.: 78281 Cov.: 29 AF XY: 0.327 AC XY: 235194 AN XY: 719386

African (AFR) AF: 0.152 AC: 5062 AN: 33232

American (AMR) AF: 0.246 AC: 10992 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 11531 AN: 25998

East Asian (EAS) AF: 0.435 AC: 17223 AN: 39568

South Asian (SAS) AF: 0.386 AC: 33121 AN: 85754

European-Finnish (FIN) AF: 0.342 AC: 18221 AN: 53352

Middle Eastern (MID) AF: 0.358 AC: 2054 AN: 5742

European-Non Finnish (NFE) AF: 0.319 AC: 350015 AN: 1095692

Other (OTH) AF: 0.334 AC: 19980 AN: 59766

GnomAD4 genome AF: 0.286 AC: 43543 AN: 152048 Hom.: 6804 Cov.: 33 AF XY: 0.294 AC XY: 21837 AN XY: 74320

African (AFR) AF: 0.157 AC: 6515 AN: 41510

American (AMR) AF: 0.286 AC: 4376 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1553 AN: 3466

East Asian (EAS) AF: 0.467 AC: 2416 AN: 5170

South Asian (SAS) AF: 0.388 AC: 1869 AN: 4822

European-Finnish (FIN) AF: 0.351 AC: 3703 AN: 10542

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22041 AN: 67946

Other (OTH) AF: 0.309 AC: 652 AN: 2112

Alfa AF: 0.278 Hom.: 2784

Bravo AF: 0.274

Asia WGS AF: 0.400 AC: 1392 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Charlevoix-Saguenay spastic ataxia (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.9
DANN	Benign	0.74
PhyloP100		0.42
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17078720; hg19: chr13-23985391; COSMIC: COSV66534551;