Variant rs9510706 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.140

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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/exons	MANE	UniProt
SACS	NM_014363.6 linkuse as main transcript	c.346-47G>A		intron_variant		ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9 linkuse as main transcript	c.346-47G>A		intron_variant		5	NM_014363.6	P1	Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2654

AN:

152052

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0177

AC XY:

1359

AN XY:

76686

show subpopulations

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.:

AF XY:

0.0237

AC XY:

10615

AN XY:

448232

show subpopulations

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.:

Cov.:

AF XY:

0.0174

AC XY:

1291

AN XY:

74394

show subpopulations

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.:

Bravo

AF:

0.0164

Asia WGS

AF:

0.00202

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 09, 2018

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over