rs11839380

Variant names:

• chr13-23335003-T-C
• rs11839380
• NM_014363.6:c.8873A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-23335003-T-C
• chr13-23335003-T-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_014363.6(SACS):​c.8873A>G​(p.Lys2958Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00422 in 1,613,794 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2958N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (143 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (111 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:10
• Conservation: PhyloP100: 5.95
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• Charlevoix-Saguenay spastic ataxia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, PanelApp Australia, G2P, Myriad Women’s Health, Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077159405).
• BP6: Variant 13-23335003-T-C is Benign according to our data. Variant chr13-23335003-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193711.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0772 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014363.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	NM_014363.6	MANE Select	c.8873A>G	p.Lys2958Arg	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.8900A>G	p.Lys2967Arg	missense	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.8432A>G	p.Lys2811Arg	missense	Exon 8 of 8	NP_001264984.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.8873A>G	p.Lys2958Arg	missense	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2432-5519A>G		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.8900A>G	p.Lys2967Arg	missense	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3476 AN: 152158 Hom.: 143 Cov.: 33

Gnomad AFR AF: 0.0794

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.00587 AC: 1474 AN: 250928 AF XY: 0.00435

Gnomad AFR exome AF: 0.0788

Gnomad AMR exome AF: 0.00365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00227 AC: 3316 AN: 1461518 Hom.: 111 Cov.: 37 AF XY: 0.00199 AC XY: 1448 AN XY: 727066

African (AFR) AF: 0.0787 AC: 2630 AN: 33430

American (AMR) AF: 0.00418 AC: 187 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86246

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53404

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5766

European-Non Finnish (NFE) AF: 0.000166 AC: 185 AN: 1111770

Other (OTH) AF: 0.00462 AC: 279 AN: 60382

GnomAD4 genome AF: 0.0229 AC: 3488 AN: 152276 Hom.: 143 Cov.: 33 AF XY: 0.0221 AC XY: 1645 AN XY: 74468

African (AFR) AF: 0.0794 AC: 3301 AN: 41550

American (AMR) AF: 0.00785 AC: 120 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68004

Other (OTH) AF: 0.0213 AC: 45 AN: 2114

Alfa AF: 0.00722 Hom.: 134

Bravo AF: 0.0262

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0744 AC: 328

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00745 AC: 904

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
1	-	1	Charlevoix-Saguenay spastic ataxia (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.33
Sift	Benign	0.82	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.34
MVP		0.88
ClinPred		0.045	T
GERP RS		5.6
Varity_R		0.10
gMVP		0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11839380; hg19: chr13-23909142;