rs746704660

Variant names:

• chr13-23355192-G-A
• rs746704660
• NM_014363.6:c.1420C>T
• SACS p.Arg474Cys

Your query was ambiguous. Multiple possible variants found:

• chr13-23355192-G-A
• chr13-23355192-G-C
• chr13-23355192-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014363.6(SACS):​c.1420C>T​(p.Arg474Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R474H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.27
• Publications: 3 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: Myriad Women's Health, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

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.1420C>T	p.Arg474Cys	missense	Exon 8 of 10	NP_055178.3
	SACS	NM_001437336.1		c.1420C>T	p.Arg474Cys	missense	Exon 8 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.979C>T	p.Arg327Cys	missense	Exon 6 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.1420C>T	p.Arg474Cys	missense	Exon 8 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.1420C>T	p.Arg474Cys	missense	Exon 8 of 11	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000402364.1	TSL:2	c.-831C>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 8	ENSP00000385844.1	Q9NZJ4-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251138 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461822 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Charlevoix-Saguenay spastic ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		4.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.69
gMVP		0.94
Mutation Taster		=7/93	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs746704660;

hg19: chr13-23929331;

COSMIC: COSV66540781;

COSMIC: COSV66540781;