NM_014363.6:c.696T>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_014363.6(SACS):c.696T>C(p.Asn232Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.354

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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (REVEL=0.044).

BP6

Variant 13-23355916-A-G is Benign according to our data. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23355916-A-G is described in CliVar as Likely_benign. Clinvar id is 1113632.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.354 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.696T>C	p.Asn232Asn	synonymous_variant	Exon 8 of 10	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.696T>C	p.Asn232Asn	synonymous_variant	Exon 8 of 10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111972

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic paraplegia

Benign:1

Dec 11, 2019

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.64

CADD

Benign

5.7

(source)

DANN

Benign

0.64

PhyloP100

0.35

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over