13-23340950-G-T

Position:

chr13-23340950-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_014363.6(SACS):c.2926C>A(p.Arg976Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,613,992 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 9.60

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027605057).

BP6

Variant 13-23340950-G-T is Benign according to our data. Variant chr13-23340950-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448199.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACS	NM_014363.6 linkuse as main transcript	c.2926C>A	p.Arg976Ser	missense_variant	10/10	ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 linkuse as main transcript	c.2926C>A	p.Arg976Ser	missense_variant	10/10	5	NM_014363.6	ENSP00000371729	P1	Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

182

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00422

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000294

AC:

AN:

251304

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00425

Gnomad AMR exome

AF:

0.000116

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

178

AN:

1461698

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00463

Gnomad4 AMR exome

AF:

0.000134

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:

0.000215

GnomAD4 genome

AF:

0.00120

AC:

182

AN:

152294

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00421

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000387

Hom.:

Bravo

AF:

0.00132

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000395

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 26, 2022	- -

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SACS p.Arg976Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs139993038) and ClinVar (classified as a VUS by Athena Diagnostics Inc). The variant was also identified in control databases in 110 of 282716 chromosomes at a frequency of 0.000389 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 105 of 24960 chromosomes (freq: 0.004207), Latino in 4 of 35424 chromosomes (freq: 0.000113) and European (non-Finnish) in 1 of 129084 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Arg976 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 14, 2022	BS1 -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 29, 2017

- -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 26, 2021

- -

SACS-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2022

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

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

.;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.028

T;T

MetaSVM

Uncertain

0.091

MutationAssessor

Benign

2.0

.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.077

T;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.96

.;D

Vest4

0.85

MVP

0.92

ClinPred

0.085

GERP RS

6.0

Varity_R

0.40

gMVP

0.81

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