rs146722795

chr13-23337095-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 7.76

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]

ACMG classification

Verdict is Benign. Variant got -9 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: {Benign=4, Likely_benign=5, Uncertain_significance=1}. 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].
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.6781C>A	p.Leu2261Ile	missense_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.6781C>A	p.Leu2261Ile	missense_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.00475 AC: 722 AN: 152130 Hom.: 5 Cov.: 33

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.: 7 AF XY: 0.00474 AC XY: 643 AN XY: 135696

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.: 23 Cov.: 37 AF XY: 0.00504 AC XY: 3667 AN XY: 727156

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.: 5 Cov.: 33 AF XY: 0.00576 AC XY: 429 AN XY: 74440

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.: 3

Bravo AF: 0.00296

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00524 AC: 45

ExAC AF: 0.00482 AC: 585

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia Uncertain:2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 04, 2020	- -
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. -
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

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	Athena Diagnostics	Dec 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SACS: BS1 -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

SACS-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.38	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
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	T
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

Other links and lift over

dbSNP: rs146722795; hg19: chr13-23911234; COSMIC: COSV104428963;