rs371534076
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_182914.3(SYNE2):c.2940+6A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,603,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000076 ( 0 hom. )
Consequence
SYNE2
NM_182914.3 splice_donor_region, intron
NM_182914.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0005017
2
Clinical Significance
Conservation
PhyloP100: -0.362
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 Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000046 (7/152256) while in subpopulation AFR AF= 0.000169 (7/41462). AF 95% confidence interval is 0.0000789. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYNE2 | NM_182914.3 | c.2940+6A>G | splice_donor_region_variant, intron_variant | ENST00000555002.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYNE2 | ENST00000555002.6 | c.2940+6A>G | splice_donor_region_variant, intron_variant | 1 | NM_182914.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152256Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000404 AC: 10AN: 247506Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134452
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GnomAD4 exome AF: 0.00000758 AC: 11AN: 1451416Hom.: 0 Cov.: 29 AF XY: 0.00000693 AC XY: 5AN XY: 721540
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152256Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74400
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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 | Aug 16, 2022 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 538344). This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. This variant is present in population databases (rs371534076, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change falls in intron 23 of the SYNE2 gene. It does not directly change the encoded amino acid sequence of the SYNE2 protein. It affects a nucleotide within the consensus splice site. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at