NM_014363.6:c.171+6C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014363.6(SACS):c.171+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,491,360 control chromosomes in the GnomAD database, including 21,150 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1705 hom., cov: 33)

Exomes 𝑓: 0.17 ( 19445 hom. )

Consequence

SACS
NM_014363.6 splice_region, intron

Scores

Splicing: ADA: 0.00001660

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.692

Publications

8 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 -20 ACMG points.

BP4

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

BP6

Variant 13-23375113-G-A is Benign according to our data. Variant chr13-23375113-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.175 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	Effect	Exon Rank	Protein	UniProt
SACS	NM_014363.6	MANE Select	c.171+6C>T	splice_region intron	N/A	NP_055178.3
SACS	NM_001437336.1		c.171+6C>T	splice_region intron	N/A	NP_001424265.1	A0A804HIQ1
SACS	NM_001278055.2		c.-183+6C>T	splice_region intron	N/A	NP_001264984.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SACS	ENST00000382292.9	TSL:5 MANE Select	c.171+6C>T	splice_region intron	N/A	ENSP00000371729.3	Q9NZJ4-1
SACS	ENST00000455470.6	TSL:1	c.171+6C>T	splice_region intron	N/A	ENSP00000406565.2	H0Y6M8
SACS	ENST00000682944.1		c.171+6C>T	splice_region intron	N/A	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20181

AN:

151732

Hom.:

1704

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0477

Gnomad AMI

AF:

0.301

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.0579

Gnomad SAS

AF:

0.0732

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.126

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.135

GnomAD2 exomes

AF:

0.162

AC:

14755

AN:

91072

AF XY:

0.153

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.245

Gnomad ASJ exome

AF:

0.134

Gnomad EAS exome

AF:

0.0546

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.176

GnomAD4 exome

AF:

0.166

AC:

222669

AN:

1339522

Hom.:

19445

Cov.:

AF XY:

0.164

AC XY:

108137

AN XY:

660346

show subpopulations

African (AFR)

AF:

0.0389

AC:

1043

AN:

26808

American (AMR)

AF:

0.231

AC:

6367

AN:

27526

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

3132

AN:

23316

East Asian (EAS)

AF:

0.0870

AC:

2460

AN:

28282

South Asian (SAS)

AF:

0.0829

AC:

6091

AN:

73496

European-Finnish (FIN)

AF:

0.157

AC:

7333

AN:

46804

Middle Eastern (MID)

AF:

0.105

AC:

558

AN:

5338

European-Non Finnish (NFE)

AF:

0.178

AC:

187540

AN:

1052938

Other (OTH)

AF:

0.148

AC:

8145

AN:

55014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

9839

19677

29516

39354

49193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6662

13324

19986

26648

33310

<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:

0.133

AC:

20184

AN:

151838

Hom.:

1705

Cov.:

AF XY:

0.132

AC XY:

9787

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.0476

AC:

1973

AN:

41428

American (AMR)

AF:

0.176

AC:

2688

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

454

AN:

3470

East Asian (EAS)

AF:

0.0580

AC:

298

AN:

5134

South Asian (SAS)

AF:

0.0731

AC:

352

AN:

4818

European-Finnish (FIN)

AF:

0.166

AC:

1752

AN:

10528

Middle Eastern (MID)

AF:

0.118

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.178

AC:

12072

AN:

67886

Other (OTH)

AF:

0.136

AC:

288

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

875

1751

2626

3502

4377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

226

452

678

904

1130

<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:

0.133

Hom.:

468

Bravo

AF:

0.131

Asia WGS

AF:

0.0890

AC:

306

AN:

3458

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 (4)

not provided (3)

not specified (3)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

6.2

(source)

DANN

Benign

0.95

PhyloP100

-0.69

PromoterAI

0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.0020

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

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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