rs139279302

Positions:

• chr13-23336139-C-A
• chr13-23336139-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014363.6(SACS):​c.7737G>T​(p.Lys2579Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K2579K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00300

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACS	NM_014363.6	c.7737G>T	p.Lys2579Asn	missense_variant	10/10	ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9	c.7737G>T	p.Lys2579Asn	missense_variant	10/10	5	NM_014363.6	ENSP00000371729	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.059
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	-0.032	T
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.30	T;T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.98	.;D
Vest4		0.79
MutPred		0.41		.;Gain of catalytic residue at Q2584 (P = 0.0012);
MVP		0.81
ClinPred		0.86	D
GERP RS		2.0
Varity_R		0.16
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs139279302; hg19: chr13-23910278;