chr13-23333770-A-C

Variant names:

• chr13-23333770-A-C
• rs17078605
• NM_014363.6:c.10106T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_014363.6(SACS):​c.10106T>G​(p.Val3369Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,546 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3369A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.32
• Publications: 35 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: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 13-23333770-A-C is Benign according to our data. Variant chr13-23333770-A-C is described in ClinVar as Benign. ClinVar VariationId is 2909409.Status of the report is criteria_provided_single_submitter, 1 stars.

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.10106T>G	p.Val3369Gly	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.10133T>G	p.Val3378Gly	missense	Exon 11 of 11	NP_001424265.1
	SACS	NM_001278055.2		c.9665T>G	p.Val3222Gly	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.10106T>G	p.Val3369Gly	missense	Exon 10 of 10	ENSP00000371729.3
	SACS	ENST00000455470.6	TSL:1	c.2432-4286T>G		intron	N/A	ENSP00000406565.2
	SACS	ENST00000682944.1		c.10133T>G	p.Val3378Gly	missense	Exon 11 of 11	ENSP00000507173.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250816 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461546 Hom.: 0 Cov.: 61 AF XY: 0.00000275 AC XY: 2 AN XY: 727062

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111792

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.59
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.4	L
PhyloP100		9.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.43
MutPred		0.59		Gain of catalytic residue at L3365 (P = 0)
MVP		0.95
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.32
gMVP		0.72
Mutation Taster		=70/30	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: rs17078605; hg19: chr13-23907909;