rs187773880
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_182961.4(SYNE1):c.21523-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000789 in 1,609,324 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00073 ( 8 hom. )
Consequence
SYNE1
NM_182961.4 splice_region, splice_polypyrimidine_tract, intron
NM_182961.4 splice_region, splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.01008
2
Clinical Significance
Conservation
PhyloP100: 0.222
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 6-152221567-A-C is Benign according to our data. Variant chr6-152221567-A-C is described in ClinVar as [Benign]. Clinvar id is 282236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152221567-A-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0013 (198/151992) while in subpopulation EAS AF= 0.0195 (101/5178). AF 95% confidence interval is 0.0164. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 198 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SYNE1 | NM_182961.4 | c.21523-8T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000367255.10 | NP_892006.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SYNE1 | ENST00000367255.10 | c.21523-8T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_182961.4 | ENSP00000356224 | P1 |
Frequencies
GnomAD3 genomes 0.00129 AC: 196AN: 151874Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00170 AC: 425AN: 249566Hom.: 4 AF XY: 0.00156 AC XY: 210AN XY: 135016
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GnomAD4 exome AF: 0.000735 AC: 1071AN: 1457332Hom.: 8 Cov.: 32 AF XY: 0.000743 AC XY: 539AN XY: 725120
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GnomAD4 genome 0.00130 AC: 198AN: 151992Hom.: 0 Cov.: 32 AF XY: 0.00135 AC XY: 100AN XY: 74298
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 24, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
not provided Benign:1
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 28, 2018 | - - |
Autosomal recessive ataxia, Beauce type Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
Find out detailed SpliceAI scores and Pangolin per-transcript scores at