13-23332188-C-T

Variant names:

• chr13-23332188-C-T
• rs116791509
• NM_014363.6:c.11688G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014363.6(SACS):​c.11688G>A​(p.Arg3896Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000729 in 1,614,002 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.329
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 13-23332188-C-T is Benign according to our data. Variant chr13-23332188-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240893.
• BP7: Synonymous conserved (PhyloP=0.329 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00409 (623/152254) while in subpopulation AFR AF = 0.0147 (610/41544). AF 95% confidence interval is 0.0137. There are 4 homozygotes in GnomAd4. There are 298 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.11688G>A	p.Arg3896Arg	synonymous	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.11715G>A	p.Arg3905Arg	synonymous	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.11247G>A	p.Arg3749Arg	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.11688G>A	p.Arg3896Arg	synonymous	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2432-2704G>A		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.11715G>A	p.Arg3905Arg	synonymous	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.00408 AC: 621 AN: 152136 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000980 AC: 246 AN: 251008 AF XY: 0.000708

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000378 AC: 553 AN: 1461748 Hom.: 2 Cov.: 35 AF XY: 0.000311 AC XY: 226 AN XY: 727170

African (AFR) AF: 0.0139 AC: 464 AN: 33472

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111936

Other (OTH) AF: 0.000828 AC: 50 AN: 60394

GnomAD4 genome AF: 0.00409 AC: 623 AN: 152254 Hom.: 4 Cov.: 33 AF XY: 0.00400 AC XY: 298 AN XY: 74436

African (AFR) AF: 0.0147 AC: 610 AN: 41544

American (AMR) AF: 0.000719 AC: 11 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00231 Hom.: 1

Bravo AF: 0.00476

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Charlevoix-Saguenay spastic ataxia (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.8
DANN	Benign	0.51
PhyloP100		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism

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: rs116791509; hg19: chr13-23906327;