chr13-23413511-A-G

Position:

• chr13-23413511-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACS	NM_014363.6	c.-501-1771T>C		intron_variant		ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9	c.-501-1771T>C		intron_variant		5	NM_014363.6	ENSP00000371729.3

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

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.359

Gnomad4 ASJ AF: 0.514

Gnomad4 EAS AF: 0.552

Gnomad4 SAS AF: 0.508

Gnomad4 FIN AF: 0.490

Gnomad4 NFE AF: 0.430

Gnomad4 OTH AF: 0.412

Alfa AF: 0.431 Hom.: 28470

Bravo AF: 0.372

Asia WGS AF: 0.491 AC: 1709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.84
DANN	Benign	0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs2148443; hg19: chr13-23987650; COSMIC: COSV66546091;