rs80132141

Positions:

chr13-23337540-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014363.6(SACS):c.6336A>C(p.Arg2112Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,613,970 control chromosomes in the GnomAD database, including 2 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 0.0031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 2 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.294

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 links:

SACS (HGNC:):

SACS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01073423).

BP6

Variant 13-23337540-T-G is Benign according to our data. Variant chr13-23337540-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448215.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=3}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACS	NM_014363.6 linkuse as main transcript	c.6336A>C	p.Arg2112Ser	missense_variant	10/10	ENST00000382292.9	NP_055178.3	Q9NZJ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 linkuse as main transcript	c.6336A>C	p.Arg2112Ser	missense_variant	10/10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.00309

AC:

470

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000805

AC:

202

AN:

250912

Hom.:

AF XY:

0.000612

AC XY:

AN XY:

135588

show subpopulations

Gnomad AFR exome

AF:

0.0110

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000278

AC:

407

AN:

1461750

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

172

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00989

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.00309

AC:

470

AN:

152220

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

207

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0105

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000494

Hom.:

Bravo

AF:

0.00353

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000988

AC:

120

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.22

.;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.73

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.29

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.43

.;B

Vest4

0.24

MutPred

0.55

.;Gain of catalytic residue at L2107 (P = 0);

MVP

0.76

ClinPred

0.012

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.17

gMVP

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over