rs9510706

Variant names:

• chr13-23365324-C-T
• rs9510706
• NM_014363.6:c.346-47G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014363.6(SACS):​c.346-47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,020,322 control chromosomes in the GnomAD database, including 357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (37 hom., cov: 32)
  • Exomes 𝑓: 0.025 (320 hom.)
• Consequence: SACS NM_014363.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.140

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 13-23365324-C-T is Benign according to our data. Variant chr13-23365324-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0174 (2653/152170) while in subpopulation NFE AF= 0.0264 (1798/68002). AF 95% confidence interval is 0.0254. There are 37 homozygotes in gnomad4. There are 1291 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6	c.346-47G>A		intron_variant	Intron 5 of 9	ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9	c.346-47G>A		intron_variant	Intron 5 of 9	5	NM_014363.6	ENSP00000371729.3

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2654 AN: 152052 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00592

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00520

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0178 AC: 2584 AN: 145166 Hom.: 39 AF XY: 0.0177 AC XY: 1359 AN XY: 76686

Gnomad AFR exome AF: 0.00537

Gnomad AMR exome AF: 0.00966

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00655

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.0266

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.0245 AC: 21308 AN: 868152 Hom.: 320 Cov.: 12 AF XY: 0.0237 AC XY: 10615 AN XY: 448232

Gnomad4 AFR exome AF: 0.00494

Gnomad4 AMR exome AF: 0.0100

Gnomad4 ASJ exome AF: 0.0231

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00689

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.0295

Gnomad4 OTH exome AF: 0.0227

GnomAD4 genome AF: 0.0174 AC: 2653 AN: 152170 Hom.: 37 Cov.: 32 AF XY: 0.0174 AC XY: 1291 AN XY: 74394

Gnomad4 AFR AF: 0.00590

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00521

Gnomad4 FIN AF: 0.0254

Gnomad4 NFE AF: 0.0264

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.0230 Hom.: 11

Bravo AF: 0.0164

Asia WGS AF: 0.00202 AC: 7 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.6
DANN	Benign	0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs9510706; hg19: chr13-23939463;