chr13-23375106-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014363.6(SACS):c.171+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,490,128 control chromosomes in the GnomAD database, including 70 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 0.013 ( 39 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 31 hom. )

Consequence

SACS
NM_014363.6 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.570

Publications

0 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: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

SACS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 13-23375106-G-A is Benign according to our data. Variant chr13-23375106-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260392.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1986/152146) while in subpopulation AFR AF = 0.042 (1745/41530). AF 95% confidence interval is 0.0404. There are 39 homozygotes in GnomAd4. There are 945 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.171+13C>T		intron_variant	Intron 3 of 9	ENST00000382292.9	NP_055178.3	Q9NZJ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 link	c.171+13C>T		intron_variant	Intron 3 of 9	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1979

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0420

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.0253

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.00347

AC:

313

AN:

90304

AF XY:

0.00333

show subpopulations

Gnomad AFR exome

AF:

0.0452

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00220

AC:

2940

AN:

1337982

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1387

AN XY:

659420

show subpopulations

African (AFR)

AF:

0.0461

AC:

1233

AN:

26726

American (AMR)

AF:

0.00315

AC:

AN:

27344

Ashkenazi Jewish (ASJ)

AF:

0.0235

AC:

547

AN:

23252

East Asian (EAS)

AF:

0.00

AC:

AN:

28200

South Asian (SAS)

AF:

0.000490

AC:

AN:

73406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46674

Middle Eastern (MID)

AF:

0.00957

AC:

AN:

5224

European-Non Finnish (NFE)

AF:

0.000634

AC:

667

AN:

1052214

Other (OTH)

AF:

0.00584

AC:

321

AN:

54942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

161

322

483

644

805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.0131

AC:

1986

AN:

152146

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

945

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0420

AC:

1745

AN:

41530

American (AMR)

AF:

0.00530

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.0274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

67962

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

100

200

299

399

499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00578

Hom.:

Bravo

AF:

0.0143

Asia WGS

AF:

0.00232

AC:

AN:

3466

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia

Uncertain:1Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 29, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.5

(source)

DANN

Benign

0.96

PhyloP100

-0.57

PromoterAI

-0.0058

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over