rs2737699

Variant names:

• chr13-23331572-A-G
• rs2737699
• NM_014363.6:c.12304T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001437336.1(SACS):​c.12331T>C​(p.Leu4111Leu) 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_001437336.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.23
• Publications: 20 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: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 130201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001437336.1. 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.12304T>C	p.Leu4102Leu	synonymous	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.12331T>C	p.Leu4111Leu	synonymous	Exon 11 of 11	NP_001424265.1
	SACS	NM_001278055.2		c.11863T>C	p.Leu3955Leu	synonymous	Exon 8 of 8	NP_001264984.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.12304T>C	p.Leu4102Leu	synonymous	Exon 10 of 10	ENSP00000371729.3
	SACS	ENST00000455470.6	TSL:1	c.2432-2088T>C		intron	N/A	ENSP00000406565.2
	SACS	ENST00000682944.1		c.12331T>C	p.Leu4111Leu	synonymous	Exon 11 of 11	ENSP00000507173.1

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

GnomAD2 exomes AF: 0.287 AC: 71855 AN: 250566 AF XY: 0.288

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 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

African (AFR) AF: 0.0851 AC: 2850 AN: 33472

American (AMR) AF: 0.378 AC: 16897 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10500 AN: 26130

East Asian (EAS) AF: 0.346 AC: 13725 AN: 39680

South Asian (SAS) AF: 0.341 AC: 29385 AN: 86240

European-Finnish (FIN) AF: 0.238 AC: 12711 AN: 53340

Middle Eastern (MID) AF: 0.326 AC: 1879 AN: 5768

European-Non Finnish (NFE) AF: 0.256 AC: 284783 AN: 1111560

Other (OTH) AF: 0.261 AC: 15756 AN: 60388

GnomAD4 genome AF: 0.226 AC: 34378 AN: 152166 Hom.: 4550 Cov.: 33 AF XY: 0.231 AC XY: 17197 AN XY: 74388

African (AFR) AF: 0.0911 AC: 3785 AN: 41536

American (AMR) AF: 0.325 AC: 4971 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1393 AN: 3470

East Asian (EAS) AF: 0.340 AC: 1755 AN: 5168

South Asian (SAS) AF: 0.354 AC: 1706 AN: 4818

European-Finnish (FIN) AF: 0.235 AC: 2485 AN: 10578

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17498 AN: 67998

Other (OTH) AF: 0.258 AC: 545 AN: 2116

Alfa AF: 0.254 Hom.: 17636

Bravo AF: 0.229

Asia WGS AF: 0.317 AC: 1103 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.268

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Charlevoix-Saguenay spastic ataxia (3)
-	-	3	not provided (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.6
DANN	Benign	0.34
PhyloP100		1.2
Mutation Taster		=100/0	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: rs2737699; hg19: chr13-23905711; COSMIC: COSV66541037;