dbSNP rs2737701: SACS:p.Gln3446Gln (chr13-23333538-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014363.6(SACS):c.10338G>A(p.Gln3446Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,613,474 control chromosomes in the GnomAD database, including 802,886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 74172 hom., cov: 31)

Exomes 𝑓: 1.0 ( 728714 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.13

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 13-23333538-C-T is Benign according to our data. Variant chr13-23333538-C-T is described in ClinVar as Benign. ClinVar VariationId is 130200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.10338G>A	p.Gln3446Gln	synonymous	Exon 10 of 10	NP_055178.3
SACS	NM_001437336.1		c.10365G>A	p.Gln3455Gln	synonymous	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
SACS	NM_001278055.2		c.9897G>A	p.Gln3299Gln	synonymous	Exon 8 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.10338G>A	p.Gln3446Gln	synonymous	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
SACS	ENST00000455470.6	TSL:1	c.2432-4054G>A		intron	N/A	ENSP00000406565.2	H0Y6M8
SACS	ENST00000682944.1		c.10365G>A	p.Gln3455Gln	synonymous	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes

AF:

0.987

AC:

150127

AN:

152098

Hom.:

74116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.955

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.996

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.995

GnomAD2 exomes

AF:

0.996

AC:

249772

AN:

250664

AF XY:

0.997

show subpopulations

Gnomad AFR exome

AF:

0.953

Gnomad AMR exome

AF:

0.998

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.997

GnomAD4 exome

AF:

0.999

AC:

1459308

AN:

1461258

Hom.:

728714

Cov.:

AF XY:

0.999

AC XY:

726061

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.957

AC:

32029

AN:

33454

American (AMR)

AF:

0.997

AC:

44586

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26116

AN:

26118

East Asian (EAS)

AF:

1.00

AC:

39676

AN:

39676

South Asian (SAS)

AF:

1.00

AC:

86215

AN:

86232

European-Finnish (FIN)

AF:

1.00

AC:

53360

AN:

53360

Middle Eastern (MID)

AF:

0.997

AC:

5748

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111397

AN:

1111560

Other (OTH)

AF:

0.997

AC:

60181

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

120

241

361

482

602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21664

43328

64992

86656

108320

<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:

0.987

AC:

150242

AN:

152216

Hom.:

74172

Cov.:

AF XY:

0.987

AC XY:

73466

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.955

AC:

39661

AN:

41534

American (AMR)

AF:

0.996

AC:

15210

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3470

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5172

AN:

5172

South Asian (SAS)

AF:

1.00

AC:

4823

AN:

4824

European-Finnish (FIN)

AF:

1.00

AC:

10620

AN:

10620

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

67982

AN:

68002

Other (OTH)

AF:

0.995

AC:

2099

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.993

Hom.:

33334

Bravo

AF:

0.985

Asia WGS

AF:

0.996

AC:

3465

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charlevoix-Saguenay spastic ataxia (5)

not specified (4)

not provided (3)

Hereditary spastic paraplegia (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.16

(source)

DANN

Benign

0.36

PhyloP100

-1.1

Mutation Taster

=94/6

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