rs138787771
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2
The NM_182961.4(SYNE1):βc.23315G>Aβ(p.Arg7772Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,613,974 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (β β ).
Frequency
Genomes: π 0.0041 ( 1 hom., cov: 31)
Exomes π: 0.0065 ( 48 hom. )
Consequence
SYNE1
NM_182961.4 missense
NM_182961.4 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 2.55
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 -15 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYNE1. . Gene score misZ -0.29069 (greater than the threshold 3.09). Trascript score misZ 3.2909 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive ataxia, Beauce type, autosomal recessive myogenic arthrogryposis multiplex congenita, Emery-Dreifuss muscular dystrophy 4, autosomal dominant, arthrogryposis multiplex congenita 3, myogenic type, autosomal dominant Emery-Dreifuss muscular dystrophy.
BP4
Computational evidence support a benign effect (MetaRNN=0.00968194).
BP6
Variant 6-152180281-C-T is Benign according to our data. Variant chr6-152180281-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152180281-C-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 631 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNE1 | NM_182961.4 | c.23315G>A | p.Arg7772Gln | missense_variant | 129/146 | ENST00000367255.10 | NP_892006.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SYNE1 | ENST00000367255.10 | c.23315G>A | p.Arg7772Gln | missense_variant | 129/146 | 1 | NM_182961.4 | ENSP00000356224 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00414 AC: 630AN: 152104Hom.: 1 Cov.: 31
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GnomAD3 exomes AF: 0.00351 AC: 881AN: 250934Hom.: 1 AF XY: 0.00363 AC XY: 492AN XY: 135604
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GnomAD4 exome AF: 0.00645 AC: 9435AN: 1461752Hom.: 48 Cov.: 32 AF XY: 0.00623 AC XY: 4529AN XY: 727178
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GnomAD4 genome AF: 0.00415 AC: 631AN: 152222Hom.: 1 Cov.: 31 AF XY: 0.00372 AC XY: 277AN XY: 74414
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | SYNE1: BP4, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 03, 2017 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 12, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2020 | This variant is associated with the following publications: (PMID: 31692161, 32075053) - |
not specified Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Apr 24, 2014 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg7701Gln (aka R7701Q, c.23102 G>A) in SYNE1 (using NM_033071.3). The variant is novel. It is a non-conservative amino acid change with a positively charged arginine being changed to a neutral, polar glutamine. The arginine at codon 7701 is not conserved across species. In silico analysis predicts a benign effect on protein structure and function (per lab report). SYNE1 encodes nesprin 1 (nuclear envelope spectrin repeat 1). Nesprin 1 and 2 are associated with the nuclear membrane and bind lamin A and emerin. These genes are highly expressed in both heart and skeletal muscle. It has been suggested that variants in SYNE1 may contribute to Emery-Dreiffus muscular dystrophy (EDMD). Using a candidate gene approach, Zang et al (2011), sequenced SYNE1 and SYNE2 (encoding nesprin 2) in 190 patients with EDMD and EDMD-like phenotypes who did not have causative variants in LMNA or EMD. This identified three patients who carried an SYNE1 missense variant that was not present in 192 control individuals. One of these patients was a compound heterozygote for a missense variant in SYNE2. Only minimal segregation analysis could be performed. The patient who was a compound heterozygote had an affected mother, who carried the SYNE2 variant and a seemingly unaffected father, who carried the SYNE1 variant. Dr. Beth McNallyβs group reported on a patient with dilated cardiomyopathy requiring heart transplant who had a missense variant in SYNE1 (p.Arg374His) (Puckelwartz et al 2010). They found that mice lacking the carboxy-terminus of nesprin-1develop cardiomyopathy with conduction system disease. SYNE1 has also been linked to autosomal recessive spinocerebellar ataxia 8. Nesprin-1 is over 8700 amino acids long. p.Arg7701Gln was observed in 47 of 8600 alleles from European Americans in the NHLBI ESP, which presumably indicated 47 of 4300 individuals were heterozygous for the variant. 12 of 4406 African American alleles (likely 6 of 2203 individuals) (as of April 23rd, 2013). - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 12, 2015 | - - |
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | - - |
Autosomal recessive ataxia, Beauce type Benign:1
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. - |
SYNE1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 03, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
N;.;D;N;D
REVEL
Benign
Sift
Uncertain
D;.;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
P;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at