13-23339758-GC-AG

Variant names:

• chr13-23339758-GC-AG
• rs797045938
• NM_014363.6:c.4117_4118delGCinsCT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM5 BP6_Very_Strong

The NM_014363.6(SACS):​c.4117_4118delGCinsCT​(p.Ala1373Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.00224 in 633 alleles, including 9 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1373P) has been classified as Likely benign.

• Frequency: GnomAD MNV: 𝑓 0.0022 Genomes: not found (cov: 33)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.86
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-23339758-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1343990.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP6: Variant 13-23339758-GC-AG is Benign according to our data. Variant chr13-23339758-GC-AG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4117_4118delGCinsCT	p.Ala1373Leu	missense	N/A	NP_055178.3
	SACS	NM_001437336.1		c.4144_4145delGCinsCT	p.Ala1382Leu	missense	N/A	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.3676_3677delGCinsCT	p.Ala1226Leu	missense	N/A	NP_001264984.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.4117_4118delGCinsCT	p.Ala1373Leu	missense	N/A	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2431+1686_2431+1687delGCinsCT		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.4144_4145delGCinsCT	p.Ala1382Leu	missense	N/A	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

GnomAD MNV AF: 0.00224 AC: 633 Hom.: 9

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797045938; hg19: chr13-23913897;