rs755740366
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_182961.4(SYNE1):c.19351C>T(p.Arg6451*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000186 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SYNE1
NM_182961.4 stop_gained
NM_182961.4 stop_gained
Scores
3
3
1
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 4.42
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 Pathogenic. Variant got 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNE1 | NM_182961.4 | c.19351C>T | p.Arg6451* | stop_gained | 104/146 | ENST00000367255.10 | NP_892006.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SYNE1 | ENST00000367255.10 | c.19351C>T | p.Arg6451* | stop_gained | 104/146 | 1 | NM_182961.4 | ENSP00000356224.5 | ||
SYNE1 | ENST00000423061.6 | c.19138C>T | p.Arg6380* | stop_gained | 103/146 | 1 | ENSP00000396024.1 | |||
SYNE1 | ENST00000367256.9 | n.3043C>T | non_coding_transcript_exon_variant | 19/61 | 1 | |||||
SYNE1 | ENST00000409694.6 | n.2935C>T | non_coding_transcript_exon_variant | 17/59 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250870Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135610
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461478Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727022
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74298
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Not reported inComputational scores
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Name
Calibrated prediction
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Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at