13-23335483-G-T

Variant names:

• chr13-23335483-G-T
• rs140551762
• NM_014363.6:c.8393C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_014363.6(SACS):​c.8393C>A​(p.Pro2798Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,613,592 control chromosomes in the GnomAD database, including 7 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. P2798R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (7 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:13 B:5
• Conservation: PhyloP100: 9.60
• Publications: 9 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09962568).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00168 (255/152196) while in subpopulation NFE AF = 0.00321 (218/67978). AF 95% confidence interval is 0.00286. There are 0 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.8393C>A	p.Pro2798Gln	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.8420C>A	p.Pro2807Gln	missense	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.7952C>A	p.Pro2651Gln	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.8393C>A	p.Pro2798Gln	missense	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2431+5962C>A		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.8420C>A	p.Pro2807Gln	missense	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00321

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00164 AC: 411 AN: 250536 AF XY: 0.00169

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000979

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00271 AC: 3963 AN: 1461396 Hom.: 7 Cov.: 37 AF XY: 0.00261 AC XY: 1900 AN XY: 727024

African (AFR) AF: 0.000358 AC: 12 AN: 33474

American (AMR) AF: 0.000626 AC: 28 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86252

European-Finnish (FIN) AF: 0.000904 AC: 48 AN: 53120

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00330 AC: 3667 AN: 1111854

Other (OTH) AF: 0.00291 AC: 176 AN: 60388

GnomAD4 genome AF: 0.00168 AC: 255 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.00150 AC XY: 112 AN XY: 74422

African (AFR) AF: 0.000409 AC: 17 AN: 41548

American (AMR) AF: 0.000458 AC: 7 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00321 AC: 218 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00253 Hom.: 1

Bravo AF: 0.00165

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00180 AC: 218

EpiCase AF: 0.00322

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	7	2	not provided (9)
1	4	-	Charlevoix-Saguenay spastic ataxia (5)
-	1	2	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	0.22
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.94
ClinPred		0.060	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.63
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs140551762; hg19: chr13-23909622; COSMIC: COSV66538488;