rs34647988
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP7BS1_Supporting
The ENST00000316724.10(BIN1):c.1461C>T(p.Ser487=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
BIN1
ENST00000316724.10 splice_region, synonymous
ENST00000316724.10 splice_region, synonymous
Scores
2
Splicing: ADA: 0.1884
2
Clinical Significance
Conservation
PhyloP100: -1.17
Genes affected
BIN1 (HGNC:1052): (bridging integrator 1) This gene encodes several isoforms of a nucleocytoplasmic adaptor protein, one of which was initially identified as a MYC-interacting protein with features of a tumor suppressor. Isoforms that are expressed in the central nervous system may be involved in synaptic vesicle endocytosis and may interact with dynamin, synaptojanin, endophilin, and clathrin. Isoforms that are expressed in muscle and ubiquitously expressed isoforms localize to the cytoplasm and nucleus and activate a caspase-independent apoptotic process. Studies in mouse suggest that this gene plays an important role in cardiac muscle development. Alternate splicing of the gene results in several transcript variants encoding different isoforms. Aberrant splice variants expressed in tumor cell lines have also been described. [provided by RefSeq, Mar 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.41).
BP7
Synonymous conserved (PhyloP=-1.17 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000722 (11/152310) while in subpopulation EAS AF= 0.000965 (5/5180). AF 95% confidence interval is 0.00038. There are 0 homozygotes in gnomad4. There are 6 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
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BIN1 | NM_139343.3 | c.1461C>T | p.Ser487= | splice_region_variant, synonymous_variant | 16/19 | ENST00000316724.10 | NP_647593.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BIN1 | ENST00000316724.10 | c.1461C>T | p.Ser487= | splice_region_variant, synonymous_variant | 16/19 | 1 | NM_139343.3 | ENSP00000316779 |
Frequencies
GnomAD3 genomes 0.0000723 AC: 11AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000800 AC: 20AN: 249988Hom.: 0 AF XY: 0.0000812 AC XY: 11AN XY: 135428
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461170Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22AN XY: 726914
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GnomAD4 genome 0.0000722 AC: 11AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74470
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Myopathy, centronuclear, 2 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 04, 2013 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 14, 2023 | This variant has not been reported in the literature in individuals affected with BIN1-related conditions. 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. 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: 158009). This variant is present in population databases (rs34647988, gnomAD 0.06%). This sequence change affects codon 487 of the BIN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BIN1 protein. It affects a nucleotide within the consensus splice site. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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