rs36061856

Variant names:

• chr13-23332894-G-A
• rs36061856
• NM_014363.6:c.10982C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014363.6(SACS):​c.10982C>T​(p.Ala3661Val) variant causes a missense change. The variant allele was found at a frequency of 0.000777 in 1,613,856 control chromosomes in the GnomAD database, including 2 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. A3661T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 6.51
• Publications: 7 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=0.009445995).
• BP6: Variant 13-23332894-G-A is Benign according to our data. Variant chr13-23332894-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212109.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00188 (287/152310) while in subpopulation AFR AF = 0.0045 (187/41576). AF 95% confidence interval is 0.00397. There are 2 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.10982C>T	p.Ala3661Val	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.11009C>T	p.Ala3670Val	missense	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.10541C>T	p.Ala3514Val	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.10982C>T	p.Ala3661Val	missense	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2432-3410C>T		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.11009C>T	p.Ala3670Val	missense	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152192 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000992 AC: 248 AN: 249986 AF XY: 0.000938

Gnomad AFR exome AF: 0.00493

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.000823

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.000662 AC: 967 AN: 1461546 Hom.: 0 Cov.: 35 AF XY: 0.000653 AC XY: 475 AN XY: 727054

African (AFR) AF: 0.00388 AC: 130 AN: 33468

American (AMR) AF: 0.00103 AC: 46 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26128

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39692

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86248

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53264

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.000567 AC: 631 AN: 1111900

Other (OTH) AF: 0.000960 AC: 58 AN: 60386

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152310 Hom.: 2 Cov.: 33 AF XY: 0.00177 AC XY: 132 AN XY: 74484

African (AFR) AF: 0.00450 AC: 187 AN: 41576

American (AMR) AF: 0.00235 AC: 36 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

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

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00123 Hom.: 2

Bravo AF: 0.00217

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00116 AC: 141

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.19	N
REVEL	Uncertain	0.33
Sift	Benign	0.092	T
Sift4G	Uncertain	0.035	D
Polyphen		0.95	P
Vest4		0.36
MVP		0.89
ClinPred		0.019	T
GERP RS		6.0
Varity_R		0.059
gMVP		0.29
Mutation Taster		=86/14	polymorphism

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: rs36061856; hg19: chr13-23907033; COSMIC: COSV104428907;