chr13-23337095-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014363.6(SACS):c.6781C>A(p.Leu2261Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00531 in 1,613,958 control chromosomes in the GnomAD database, including 28 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 0.0047 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 23 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 7.76

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010582924).

BP6

Variant 13-23337095-G-T is Benign according to our data. Variant chr13-23337095-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240901.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5, Likely_benign=3}. Variant chr13-23337095-G-T is described in Lovd as [Likely_pathogenic]. Variant chr13-23337095-G-T is described in Lovd as [Likely_benign]. Variant chr13-23337095-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00474 (722/152248) while in subpopulation NFE AF= 0.00543 (369/68004). AF 95% confidence interval is 0.00497. There are 5 homozygotes in gnomad4. There are 429 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.6781C>A	p.Leu2261Ile	missense_variant	Exon 10 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.6781C>A	p.Leu2261Ile	missense_variant	Exon 10 of 10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.00475

AC:

722

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0258

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00543

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00477

AC:

1198

AN:

250910

Hom.:

AF XY:

0.00474

AC XY:

643

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.000744

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0210

Gnomad NFE exome

AF:

0.00622

Gnomad OTH exome

AF:

0.00295

GnomAD4 exome

AF:

0.00536

AC:

7841

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00504

AC XY:

3667

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0201

Gnomad4 NFE exome

AF:

0.00586

Gnomad4 OTH exome

AF:

0.00343

GnomAD4 genome

AF:

0.00474

AC:

722

AN:

152248

Hom.:

Cov.:

AF XY:

0.00576

AC XY:

429

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0258

Gnomad4 NFE

AF:

0.00543

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00470

Hom.:

Bravo

AF:

0.00296

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00524

AC:

ExAC

AF:

0.00482

AC:

585

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00398

EpiControl

AF:

0.00593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia

Uncertain:2Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 04, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Leu266Ile variant was identified in the proband in trans with the SACS p.Thr458Ile variant of uncertain significance. The p.Leu2261Ile variant was previously identified in the literature, in compound heterozygous state with the p.Ser527* variant in a male patient with juvenile onset motor neuropathy, ataxia, and spasticity; these variants were considered causative (Bansagi_2017_PMID:28251916). The p.Leu2261Ile variant was also identified in compound heterozygous form (with p.Ser527*) in two affected siblings with disease onset in their 40s; the variants were reported as confirmed pathogenic. Both siblings were affected by gait disturbance and cerebellar ataxia. In addition, one sibling (male) was positive for demyelinating sensorimotor neuropathy, and MRI indicated generalized atrophy. The other sibling (female) was observed to have jerky ocular pursuit and optic atrophy (Pyle_2015_PMID:25497598). The variant was identified in dbSNP (rs146722795) and ClinVar (Conflicting interpretations of pathogenicity. Uncertain significance [1], benign [2], likely benign [2]. Classified as Uncertain significance for ARSACS in 2016 by Ilumina, likely benign in 2014 by Genome Diagnostics Centre and University Medical Centre Utrecht for ARSACS, Benign for spastic paraplegia in 2017 by Erasmus Medical Centre, Benign in 2017 by Invitae, and Likely benign in 2017 by Athena Diagnostics) databases. The variant was identified in control databases in 1397 of 282308 chromosomes (8 homozygous) at a frequency of 0.004948 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 542 of 25098 chromosomes (freq: 0.0216), European (non-Finnish) in 792 of 128852 chromosomes (freq: 0.006147), Other in 27 of 7194 chromosomes (freq: 0.003753), African in 26 of 24834 chromosomes (freq: 0.001047), Latino in 10 of 35420 chromosomes (freq: 0.000282), but was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Leu266 residue is conserved in mammals and other organisms; computational analyses (MUT Assessor, SIFT, Polyphen 2, MT, FATHMM, DANN, MetaLR, Revel) predict a deleterious impact to the protein. 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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2020	This variant is associated with the following publications: (PMID: 23280630, 19779133, 24457356, 28251916, 25497598) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2025	SACS: BS1, BS2 -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2024

- -

SACS-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 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). -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.88

N;N

REVEL

Pathogenic

0.79

Sift

Benign

0.17

T;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.82

.;P

Vest4

0.67

MVP

0.85

ClinPred

0.019

GERP RS

5.8

Varity_R

0.16

gMVP

0.43

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