rs1268605937
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The ENST00000211998.10(VCL):c.3258+4T>C 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 0.0000028 in 1,430,074 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: not found (cov: 29)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
VCL
ENST00000211998.10 splice_donor_region, intron
ENST00000211998.10 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00001193
2
Clinical Significance
Conservation
PhyloP100: -1.81
Genes affected
VCL (HGNC:12665): (vinculin) Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane. Defects in VCL are the cause of cardiomyopathy dilated type 1W. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]
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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=-0.84).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.3258+4T>C | splice_donor_region_variant, intron_variant | ENST00000211998.10 | NP_054706.1 | |||
VCL | NM_003373.4 | c.3054+4T>C | splice_donor_region_variant, intron_variant | NP_003364.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VCL | ENST00000211998.10 | c.3258+4T>C | splice_donor_region_variant, intron_variant | 1 | NM_014000.3 | ENSP00000211998 | ||||
VCL | ENST00000372755.7 | c.3054+4T>C | splice_donor_region_variant, intron_variant | 1 | ENSP00000361841 | P1 | ||||
VCL | ENST00000623461.3 | n.5857+4T>C | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 1 | ||||||
VCL | ENST00000624354.3 | c.*3013+4T>C | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 2 | ENSP00000485551 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD3 genomes
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29
GnomAD3 exomes AF: 0.0000203 AC: 4AN: 196946Hom.: 0 AF XY: 0.0000287 AC XY: 3AN XY: 104686
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GnomAD4 exome AF: 0.00000280 AC: 4AN: 1430074Hom.: 0 Cov.: 31 AF XY: 0.00000424 AC XY: 3AN XY: 708240
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GnomAD4 genome Cov.: 29
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dilated cardiomyopathy 1W Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 07, 2019 | This sequence change falls in intron 21 of the VCL gene. It does not directly change the encoded amino acid sequence of the VCL protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VCL-related disease. ClinVar contains an entry for this variant (Variation ID: 536717). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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
Calibrated prediction
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Prediction
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