dbSNP rs1536365: SACS:p.Leu552Leu (chr13-23354956-T-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_014363.6(SACS):c.1656A>G(p.Leu552Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,152 control chromosomes in the GnomAD database, including 11,253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L552L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.088 ( 784 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10469 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.212

Publications

15 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: Myriad Women's Health, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Laboratory for Molecular Medicine, Orphanet

SACS links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_014363.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.03).

BP6

Variant 13-23354956-T-C is Benign according to our data. Variant chr13-23354956-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.212 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.121 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.1656A>G	p.Leu552Leu	synonymous	Exon 8 of 10	NP_055178.3
SACS	NM_001437336.1		c.1656A>G	p.Leu552Leu	synonymous	Exon 8 of 11	NP_001424265.1	A0A804HIQ1
SACS	NM_001278055.2		c.1215A>G	p.Leu405Leu	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.1656A>G	p.Leu552Leu	synonymous	Exon 8 of 10	ENSP00000371729.3	Q9NZJ4-1
SACS	ENST00000455470.6	TSL:1	c.1656A>G	p.Leu552Leu	synonymous	Exon 8 of 11	ENSP00000406565.2	H0Y6M8
SACS	ENST00000402364.1	TSL:2	c.-595A>G		5_prime_UTR_premature_start_codon_gain	Exon 6 of 8	ENSP00000385844.1	Q9NZJ4-2

Frequencies

GnomAD3 genomes

AF:

0.0886

AC:

13478

AN:

152192

Hom.:

783

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0786

Gnomad ASJ

AF:

0.0822

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.155

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.0957

GnomAD2 exomes

AF:

0.112

AC:

28125

AN:

251274

AF XY:

0.116

show subpopulations

Gnomad AFR exome

AF:

0.0177

Gnomad AMR exome

AF:

0.0826

Gnomad ASJ exome

AF:

0.0807

Gnomad EAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.115

GnomAD4 exome

AF:

0.116

AC:

169589

AN:

1461842

Hom.:

10469

Cov.:

AF XY:

0.117

AC XY:

85027

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0174

AC:

583

AN:

33480

American (AMR)

AF:

0.0814

AC:

3640

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0806

AC:

2107

AN:

26134

East Asian (EAS)

AF:

0.135

AC:

5344

AN:

39700

South Asian (SAS)

AF:

0.130

AC:

11253

AN:

86258

European-Finnish (FIN)

AF:

0.163

AC:

8682

AN:

53400

Middle Eastern (MID)

AF:

0.102

AC:

591

AN:

5768

European-Non Finnish (NFE)

AF:

0.118

AC:

130716

AN:

1111984

Other (OTH)

AF:

0.110

AC:

6673

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

9973

19946

29920

39893

49866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4654

9308

13962

18616

23270

<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:

0.0885

AC:

13479

AN:

152310

Hom.:

784

Cov.:

AF XY:

0.0902

AC XY:

6721

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0201

AC:

836

AN:

41572

American (AMR)

AF:

0.0785

AC:

1201

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0822

AC:

285

AN:

3466

East Asian (EAS)

AF:

0.127

AC:

661

AN:

5186

South Asian (SAS)

AF:

0.130

AC:

626

AN:

4828

European-Finnish (FIN)

AF:

0.155

AC:

1647

AN:

10616

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.117

AC:

7992

AN:

68024

Other (OTH)

AF:

0.0942

AC:

199

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

634

1268

1901

2535

3169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<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:

0.104

Hom.:

1697

Bravo

AF:

0.0796

Asia WGS

AF:

0.113

AC:

392

AN:

3478

EpiCase

AF:

0.112

EpiControl

AF:

0.113

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charlevoix-Saguenay spastic ataxia (5)

not provided (3)

not specified (3)

Hereditary spastic paraplegia (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

8.0

(source)

DANN

Benign

0.55

PhyloP100

-0.21

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=283/17

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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