chr6-152208032-ACTCATGGGGAGGTAGGACACTTCAACCAACCATTTACGAAGCTTTTCTGCCATCT-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_182961.4(SYNE1):c.22709_22763delAGATGGCAGAAAAGCTTCGTAAATGGTTGGTTGAAGTGTCCTACCTCCCCATGAG(p.Glu7570fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SYNE1
NM_182961.4 frameshift
NM_182961.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.96
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 18 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;
PP5
Variant 6-152208032-ACTCATGGGGAGGTAGGACACTTCAACCAACCATTTACGAAGCTTTTCTGCCATCT-A is Pathogenic according to our data. Variant chr6-152208032-ACTCATGGGGAGGTAGGACACTTCAACCAACCATTTACGAAGCTTTTCTGCCATCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152208032-ACTCATGGGGAGGTAGGACACTTCAACCAACCATTTACGAAGCTTTTCTGCCATCT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SYNE1 | NM_182961.4 | c.22709_22763delAGATGGCAGAAAAGCTTCGTAAATGGTTGGTTGAAGTGTCCTACCTCCCCATGAG | p.Glu7570fs | frameshift_variant | 125/146 | ENST00000367255.10 | NP_892006.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461876Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727240
GnomAD4 exome
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727240
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2018 | A variant that is likely pathogenic has been identified in the SYNE1 gene. The c.22496_22550del55 variant in the SYNE1 gene causes a frameshift starting with codon Glutamic acid 7499, changes this amino acid to a Valine residue and creates a premature Stop codon at position 36 of the new reading frame, denoted p.Glu7499ValfsX36. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 28, 2016 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at