rs144362131

Variant names:

• chr13-23341100-T-C
• rs144362131
• NM_014363.6:c.2776A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_014363.6(SACS):​c.2776A>G​(p.Ile926Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.70
• 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, PanelApp Australia, G2P, Myriad Women’s Health, Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1033518).
• BP6: Variant 13-23341100-T-C is Benign according to our data. Variant chr13-23341100-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 586429.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000114 (166/1461498) while in subpopulation MID AF = 0.00676 (39/5768). AF 95% confidence interval is 0.00508. There are 0 homozygotes in GnomAdExome4. There are 76 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check.

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.2776A>G	p.Ile926Val	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.2803A>G	p.Ile935Val	missense	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.2335A>G	p.Ile779Val	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.2776A>G	p.Ile926Val	missense	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2431+345A>G		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.2803A>G	p.Ile935Val	missense	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 250868 AF XY: 0.000192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1461498 Hom.: 0 Cov.: 36 AF XY: 0.000105 AC XY: 76 AN XY: 727040

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39684

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.0000648 AC: 72 AN: 1111966

Other (OTH) AF: 0.000282 AC: 17 AN: 60388

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74506

African (AFR) AF: 0.0000240 AC: 1 AN: 41588

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.28
Sift	Benign	0.078	T
Sift4G	Benign	0.31	T
Polyphen		0.014	B
Vest4		0.19
MVP		0.69
ClinPred		0.0096	T
GERP RS		3.6
Varity_R		0.027
gMVP		0.45
Mutation Taster		=91/9	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: rs144362131; hg19: chr13-23915239;