13-23335023-A-G

Variant names:

• chr13-23335023-A-G
• rs9552929
• NM_014363.6:c.8853T>C
• SACS p.Val2951Val

Variant summary

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

The NM_014363.6(SACS):​c.8853T>C​(p.Val2951Val) 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:15
• Conservation: PhyloP100: 0.156
• Publications: 19 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: Myriad Women's Health, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 130205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.8853T>C	p.Val2951Val	synonymous	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.8880T>C	p.Val2960Val	synonymous	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.8412T>C	p.Val2804Val	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.8853T>C	p.Val2951Val	synonymous	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2432-5539T>C		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.8880T>C	p.Val2960Val	synonymous	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

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

GnomAD2 exomes AF: 0.287 AC: 71940 AN: 250780 AF XY: 0.288

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 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

African (AFR) AF: 0.0856 AC: 2859 AN: 33416

American (AMR) AF: 0.378 AC: 16896 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10481 AN: 26094

East Asian (EAS) AF: 0.345 AC: 13702 AN: 39686

South Asian (SAS) AF: 0.341 AC: 29430 AN: 86220

European-Finnish (FIN) AF: 0.239 AC: 12738 AN: 53364

Middle Eastern (MID) AF: 0.326 AC: 1879 AN: 5762

European-Non Finnish (NFE) AF: 0.256 AC: 284949 AN: 1111574

Other (OTH) AF: 0.261 AC: 15757 AN: 60364

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

African (AFR) AF: 0.0915 AC: 3801 AN: 41550

American (AMR) AF: 0.326 AC: 4985 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1392 AN: 3470

East Asian (EAS) AF: 0.339 AC: 1753 AN: 5178

South Asian (SAS) AF: 0.354 AC: 1710 AN: 4824

European-Finnish (FIN) AF: 0.235 AC: 2497 AN: 10606

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17489 AN: 67960

Other (OTH) AF: 0.258 AC: 545 AN: 2112

Alfa AF: 0.258 Hom.: 8961

Bravo AF: 0.230

Asia WGS AF: 0.317 AC: 1103 AN: 3478

EpiCase AF: 0.265

EpiControl AF: 0.268

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.72
CADD	Benign	0.45
DANN	Benign	0.62
PhyloP100		0.16
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs9552929;

hg19: chr13-23909162;

COSMIC: COSV104428861;