rs751888795

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_014363.6(SACS):ā€‹c.8956C>Gā€‹(p.His2986Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000096 ( 0 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.46
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28149444).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SACSNM_014363.6 linkuse as main transcriptc.8956C>G p.His2986Asp missense_variant 10/10 ENST00000382292.9 NP_055178.3 Q9NZJ4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SACSENST00000382292.9 linkuse as main transcriptc.8956C>G p.His2986Asp missense_variant 10/105 NM_014363.6 ENSP00000371729.3 Q9NZJ4-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152102
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250636
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135418
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461638
Hom.:
0
Cov.:
37
AF XY:
0.00000550
AC XY:
4
AN XY:
727114
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152102
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 12, 2022This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 2986 of the SACS protein (p.His2986Asp). This variant is present in population databases (rs751888795, gnomAD 0.003%). This missense change has been observed in individual(s) with spastic ataxia (PMID: 28454995). ClinVar contains an entry for this variant (Variation ID: 558044). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SACS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Charlevoix-Saguenay spastic ataxia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylApr 25, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
0.010
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.26
.;T
Eigen
Benign
-0.053
Eigen_PC
Benign
0.091
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.28
T;T
MetaSVM
Benign
-0.42
T
MutationAssessor
Benign
1.4
.;L
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.75
N;N
REVEL
Uncertain
0.50
Sift
Benign
0.44
T;T
Sift4G
Uncertain
0.019
D;D
Polyphen
0.61
.;P
Vest4
0.52
MutPred
0.48
.;Gain of catalytic residue at M2989 (P = 0.0224);
MVP
0.77
ClinPred
0.23
T
GERP RS
4.8
Varity_R
0.16
gMVP
0.79

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs751888795; hg19: chr13-23909059; API