13-23336348-C-T

Position:

chr13-23336348-C-T

Variant summary

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

The NM_014363.6(SACS):c.7528G>A(p.Ala2510Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,096 control chromosomes in the GnomAD database, including 4 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 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 3 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:5

Conservation

PhyloP100: 7.57

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:

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=0.04148993).

BP6

Variant 13-23336348-C-T is Benign according to our data. Variant chr13-23336348-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260399.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4}.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6 linkuse as main transcript	c.7528G>A	p.Ala2510Thr	missense_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9 linkuse as main transcript	c.7528G>A	p.Ala2510Thr	missense_variant	10/10	5	NM_014363.6	P1	Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

190

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00125

AC:

313

AN:

251312

Hom.:

AF XY:

0.00116

AC XY:

157

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00206

AC:

3014

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

1448

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000788

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00251

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00125

AC:

190

AN:

152304

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00206

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00198

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00124

AC:

151

EpiCase

AF:

0.00191

EpiControl

AF:

0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2023	Observed with two other SACS variants, phase unknown, in an individual with rigidity, bradykinesia, slow speech production, and abnormal brain MRI in the published literature (Wagner et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23280630, 35008978, 29379980) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	SACS: BS2 -

Charlevoix-Saguenay spastic ataxia

Uncertain:2Benign:1

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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 21, 2021

- -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 23, 2021

- -

SACS-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

.;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.041

T;T

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.4

.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.36

N;N

REVEL

Uncertain

0.57

Sift

Uncertain

0.022

D;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.98

.;D

Vest4

0.79

MVP

0.93

ClinPred

0.037

GERP RS

5.7

Varity_R

0.18

gMVP

0.70

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