rs141716975
Positions:
Variant summary
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).
Frequency
Genomes: 𝑓 0.0043 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0059 ( 33 hom. )
Consequence
SYNE1
NM_182961.4 missense
NM_182961.4 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 5.92
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 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=0.0070774257).
BP6
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=7, Uncertain_significance=1, Benign=4}. Variant chr6-152148069-G-A is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 652 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNE1 | NM_182961.4 | c.24952C>T | p.Leu8318Phe | missense_variant | 137/146 | ENST00000367255.10 | NP_892006.3 | |
SYNE1 | NM_001347702.2 | c.1417C>T | p.Leu473Phe | missense_variant | 8/18 | ENST00000354674.5 | NP_001334631.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SYNE1 | ENST00000367255.10 | c.24952C>T | p.Leu8318Phe | missense_variant | 137/146 | 1 | NM_182961.4 | ENSP00000356224.5 | ||
SYNE1 | ENST00000354674.5 | c.1417C>T | p.Leu473Phe | missense_variant | 8/18 | 5 | NM_001347702.2 | ENSP00000346701.4 |
Frequencies
GnomAD3 genomes AF: 0.00428 AC: 651AN: 152170Hom.: 1 Cov.: 33
GnomAD3 genomes
AF:
AC:
651
AN:
152170
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00508 AC: 1269AN: 249678Hom.: 4 AF XY: 0.00527 AC XY: 712AN XY: 135050
GnomAD3 exomes
AF:
AC:
1269
AN:
249678
Hom.:
AF XY:
AC XY:
712
AN XY:
135050
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00590 AC: 8623AN: 1461796Hom.: 33 Cov.: 36 AF XY: 0.00592 AC XY: 4306AN XY: 727192
GnomAD4 exome
AF:
AC:
8623
AN:
1461796
Hom.:
Cov.:
36
AF XY:
AC XY:
4306
AN XY:
727192
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00428 AC: 652AN: 152288Hom.: 1 Cov.: 33 AF XY: 0.00415 AC XY: 309AN XY: 74462
GnomAD4 genome
AF:
AC:
652
AN:
152288
Hom.:
Cov.:
33
AF XY:
AC XY:
309
AN XY:
74462
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
19
ALSPAC
AF:
AC:
37
ESP6500AA
AF:
AC:
3
ESP6500EA
AF:
AC:
48
ExAC
AF:
AC:
643
Asia WGS
AF:
AC:
6
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:14
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:8
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 16, 2018 | - - |
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+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | SYNE1: BP4, BS2 - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 07, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Autosomal recessive ataxia, Beauce type Benign:2
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. - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
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. - |
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 28, 2024 | - - |
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
Uncertain
T;.;.;T;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;D;D;N;N;N
REVEL
Benign
Sift
Uncertain
D;.;D;D;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T
Polyphen
P;.;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at