rs965275563
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS2_Supporting
The NM_182961.4(SYNE1):āc.18842A>Cā(p.Glu6281Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000034 ( 0 hom. )
Consequence
SYNE1
NM_182961.4 missense
NM_182961.4 missense
Scores
1
3
15
Clinical Significance
Conservation
PhyloP100: 6.35
Genes affected
SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, SYNE1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.19046497).
BS2
?
High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYNE1 | NM_182961.4 | c.18842A>C | p.Glu6281Ala | missense_variant | 101/146 | ENST00000367255.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYNE1 | ENST00000367255.10 | c.18842A>C | p.Glu6281Ala | missense_variant | 101/146 | 1 | NM_182961.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461628Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727114
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74252
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 10, 2022 | This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 586719). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 6210 of the SYNE1 protein (p.Glu6210Ala). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 03, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N
REVEL
Benign
Sift
Benign
T;.;T
Sift4G
Benign
T;T;T
Polyphen
B;.;.
Vest4
MutPred
Loss of catalytic residue at E6281 (P = 0.0844);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at