chr2-127062111-G-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_139343.3(BIN1):c.857+4C>T 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 0.0000387 in 1,603,684 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 0.000098 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 0 hom. )
Consequence
BIN1
NM_139343.3 splice_donor_region, intron
NM_139343.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0002946
2
Clinical Significance
Conservation
PhyloP100: -1.76
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 -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000324 (47/1451356) while in subpopulation SAS AF= 0.000344 (29/84312). AF 95% confidence interval is 0.000246. There are 0 homozygotes in gnomad4_exome. There are 34 alleles in male gnomad4_exome subpopulation. Median coverage is 32. 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.857+4C>T | splice_donor_region_variant, intron_variant | ENST00000316724.10 | NP_647593.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BIN1 | ENST00000316724.10 | c.857+4C>T | splice_donor_region_variant, intron_variant | 1 | NM_139343.3 | ENSP00000316779 |
Frequencies
GnomAD3 genomes 0.0000985 AC: 15AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000855 AC: 20AN: 233880Hom.: 0 AF XY: 0.000111 AC XY: 14AN XY: 126556
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GnomAD4 exome AF: 0.0000324 AC: 47AN: 1451356Hom.: 0 Cov.: 32 AF XY: 0.0000472 AC XY: 34AN XY: 721022
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GnomAD4 genome 0.0000985 AC: 15AN: 152328Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74494
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Myopathy, centronuclear, 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 12, 2024 | This sequence change falls in intron 10 of the BIN1 gene. It does not directly change the encoded amino acid sequence of the BIN1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs61748156, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with BIN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 530865). 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. 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
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Name
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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