rs750371615
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_182914.3(SYNE2):āc.8249T>Gā(p.Leu2750Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.000011 ( 0 hom. )
Consequence
SYNE2
NM_182914.3 missense
NM_182914.3 missense
Scores
1
5
12
Clinical Significance
Conservation
PhyloP100: 1.44
Genes affected
SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000109 (16/1461854) while in subpopulation AMR AF= 0.000268 (12/44724). AF 95% confidence interval is 0.000154. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAdExome4 at 16 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYNE2 | NM_182914.3 | c.8249T>G | p.Leu2750Arg | missense_variant | 48/116 | ENST00000555002.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYNE2 | ENST00000555002.6 | c.8249T>G | p.Leu2750Arg | missense_variant | 48/116 | 1 | NM_182914.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000642 AC: 16AN: 249318Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135266
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461854Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727230
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Emery-Dreifuss muscular dystrophy 5, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2750 of the SYNE2 protein (p.Leu2750Arg). This variant is present in population databases (rs750371615, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 576405). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;M;.
MutationTaster
Benign
N;N;N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;D;D
REVEL
Uncertain
Sift
Uncertain
D;.;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;.;D;.
Vest4
MutPred
Gain of solvent accessibility (P = 0.0584);.;Gain of solvent accessibility (P = 0.0584);.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at