Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_182961.4(SYNE1):c.24952C>T(p.Leu8318Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00575 in 1,614,084 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L8318R) has been classified as Uncertain significance.
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]
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, SYNE1
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.0070774257).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-152148069-G-A is Benign according to our data. Variant chr6-152148069-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194303.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=4, Uncertain_significance=1}. Variant chr6-152148069-G-A is described in Lovd as [Likely_benign].
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Likely benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Oct 26, 2023
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Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Feb 01, 2024
SYNE1: BP4, BS2 -
Benign, criteria provided, single submitter
clinical testing
Athena Diagnostics
Jan 16, 2018
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Likely benign, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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Likely benign, no assertion criteria provided
clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
-
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Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Apr 16, 2021
Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, no assertion criteria provided
clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
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not specified Benign:2
Benign, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Jan 07, 2015
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Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
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Autosomal recessive ataxia, Beauce type Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
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Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Oct 21, 2021
The c.24739C>T (p.L8247F) alteration is located in exon 136 (coding exon 135) of the SYNE1 gene. This alteration results from a C to T substitution at nucleotide position 24739, causing the leucine (L) at amino acid position 8247 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
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. -