13-23354773-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BA1

The NM_014363.6(SACS):c.1839G>A(p.Gln613Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00504 in 1,614,054 control chromosomes in the GnomAD database, including 320 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 0.026 ( 171 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 149 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:9

Conservation

PhyloP100: 1.22

Publications

1 publications found

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 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

SACS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.057).

BP6

Variant 13-23354773-C-T is Benign according to our data. Variant chr13-23354773-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260394.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0887 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SACS	NM_014363.6	MANE Select	c.1839G>A	p.Gln613Gln	synonymous	Exon 8 of 10	NP_055178.3
SACS	NM_001437336.1		c.1839G>A	p.Gln613Gln	synonymous	Exon 8 of 11	NP_001424265.1	A0A804HIQ1
SACS	NM_001278055.2		c.1398G>A	p.Gln466Gln	synonymous	Exon 6 of 8	NP_001264984.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SACS	ENST00000382292.9	TSL:5 MANE Select	c.1839G>A	p.Gln613Gln	synonymous	Exon 8 of 10	ENSP00000371729.3	Q9NZJ4-1
SACS	ENST00000455470.6	TSL:1	c.1839G>A	p.Gln613Gln	synonymous	Exon 8 of 11	ENSP00000406565.2	H0Y6M8
SACS	ENST00000682944.1		c.1839G>A	p.Gln613Gln	synonymous	Exon 8 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes

AF:

0.0263

AC:

4005

AN:

152194

Hom.:

170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0911

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00955

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.00721

AC:

1810

AN:

251178

AF XY:

0.00541

show subpopulations

Gnomad AFR exome

AF:

0.0951

Gnomad AMR exome

AF:

0.00472

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000616

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00281

AC:

4114

AN:

1461742

Hom.:

149

Cov.:

AF XY:

0.00248

AC XY:

1806

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.0925

AC:

3096

AN:

33480

American (AMR)

AF:

0.00519

AC:

232

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000267

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.0000750

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000317

AC:

352

AN:

1111958

Other (OTH)

AF:

0.00608

AC:

367

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

247

494

740

987

1234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0264

AC:

4019

AN:

152312

Hom.:

171

Cov.:

AF XY:

0.0262

AC XY:

1954

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0911

AC:

3788

AN:

41558

American (AMR)

AF:

0.00948

AC:

145

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68034

Other (OTH)

AF:

0.0203

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

188

375

563

750

938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0113

Hom.:

Bravo

AF:

0.0302

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charlevoix-Saguenay spastic ataxia (3)

not provided (3)

not specified (2)

Hereditary spastic paraplegia (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.8

(source)

DANN

Benign

0.69

PhyloP100

1.2

Mutation Taster

=284/16

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over