NM_014363.6:c.2080G>A

Variant names:

• chr13-23354532-C-T
• rs17325713
• NM_014363.6:c.2080G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014363.6(SACS):​c.2080G>A​(p.Ala694Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0314 in 1,613,750 control chromosomes in the GnomAD database, including 948 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (79 hom., cov: 33)
  • Exomes 𝑓: 0.032 (869 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 6.06
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026889741).
• BP6: Variant 13-23354532-C-T is Benign according to our data. Variant chr13-23354532-C-T is described in ClinVar as Benign. ClinVar VariationId is 240895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0244 (3719/152226) while in subpopulation NFE AF = 0.039 (2654/68000). AF 95% confidence interval is 0.0378. There are 79 homozygotes in GnomAd4. There are 1721 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 79 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	NM_014363.6	MANE Select	c.2080G>A	p.Ala694Thr	missense	Exon 8 of 10	NP_055178.3
	SACS	NM_001437336.1		c.2080G>A	p.Ala694Thr	missense	Exon 8 of 11	NP_001424265.1
	SACS	NM_001278055.2		c.1639G>A	p.Ala547Thr	missense	Exon 6 of 8	NP_001264984.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.2080G>A	p.Ala694Thr	missense	Exon 8 of 10	ENSP00000371729.3
	SACS	ENST00000455470.6	TSL:1	c.2080G>A	p.Ala694Thr	missense	Exon 8 of 11	ENSP00000406565.2
	SACS	ENST00000682944.1		c.2080G>A	p.Ala694Thr	missense	Exon 8 of 11	ENSP00000507173.1

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3719 AN: 152108 Hom.: 79 Cov.: 33

Gnomad AFR AF: 0.00579

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.0434

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0390

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0240 AC: 6022 AN: 250596 AF XY: 0.0238

Gnomad AFR exome AF: 0.00428

Gnomad AMR exome AF: 0.00934

Gnomad ASJ exome AF: 0.00993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0486

Gnomad NFE exome AF: 0.0363

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0322 AC: 47021 AN: 1461524 Hom.: 869 Cov.: 32 AF XY: 0.0319 AC XY: 23170 AN XY: 727078

African (AFR) AF: 0.00439 AC: 147 AN: 33478

American (AMR) AF: 0.00894 AC: 400 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 264 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00828 AC: 714 AN: 86252

European-Finnish (FIN) AF: 0.0464 AC: 2477 AN: 53368

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5762

European-Non Finnish (NFE) AF: 0.0372 AC: 41377 AN: 1111726

Other (OTH) AF: 0.0268 AC: 1618 AN: 60380

GnomAD4 genome AF: 0.0244 AC: 3719 AN: 152226 Hom.: 79 Cov.: 33 AF XY: 0.0231 AC XY: 1721 AN XY: 74426

African (AFR) AF: 0.00578 AC: 240 AN: 41546

American (AMR) AF: 0.0165 AC: 252 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4824

European-Finnish (FIN) AF: 0.0434 AC: 460 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0390 AC: 2654 AN: 68000

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.0325 Hom.: 382

Bravo AF: 0.0198

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0370 AC: 318

ExAC AF: 0.0232 AC: 2817

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.0323

EpiControl AF: 0.0316

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		6.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.084
Sift	Benign	0.36	T
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.046
ClinPred		0.034	T
GERP RS		5.2
Varity_R		0.077
gMVP		0.29
Mutation Taster		=287/13	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: rs17325713; hg19: chr13-23928671; COSMIC: COSV99063575;