rs2148443

Variant names:

• chr13-23413511-A-G
• rs2148443
• NM_014363.6:c.-501-1771T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014363.6(SACS):​c.-501-1771T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 152,016 control chromosomes in the GnomAD database, including 12,112 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (12112 hom., cov: 32)
• Consequence: SACS NM_014363.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.264
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.535 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.-501-1771T>C		intron	N/A	NP_055178.3
	SACS	NM_001437336.1		c.-501-1771T>C		intron	N/A	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.-501-1771T>C		intron	N/A	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.-501-1771T>C		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.-501-1771T>C		intron	N/A	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59322 AN: 151896 Hom.: 12108 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.414

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.390 AC: 59355 AN: 152016 Hom.: 12112 Cov.: 32 AF XY: 0.398 AC XY: 29577 AN XY: 74312

African (AFR) AF: 0.267 AC: 11056 AN: 41472

American (AMR) AF: 0.359 AC: 5476 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1782 AN: 3470

East Asian (EAS) AF: 0.552 AC: 2857 AN: 5174

South Asian (SAS) AF: 0.508 AC: 2452 AN: 4824

European-Finnish (FIN) AF: 0.490 AC: 5167 AN: 10546

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.430 AC: 29231 AN: 67950

Other (OTH) AF: 0.412 AC: 870 AN: 2114

Alfa AF: 0.418 Hom.: 43061

Bravo AF: 0.372

Asia WGS AF: 0.491 AC: 1709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.84
DANN	Benign	0.38
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2148443; hg19: chr13-23987650; COSMIC: COSV66546091;