10-74072856-C-G
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_014000.3(VCL):c.622+4C>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 0.0000211 in 1,613,860 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )
Consequence
VCL
NM_014000.3 splice_donor_region, intron
NM_014000.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0005039
2
Clinical Significance
Conservation
PhyloP100: -0.111
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 Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BS2
?
High AC in GnomAd at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.622+4C>G | splice_donor_region_variant, intron_variant | ENST00000211998.10 | |||
VCL | NM_003373.4 | c.622+4C>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCL | ENST00000211998.10 | c.622+4C>G | splice_donor_region_variant, intron_variant | 1 | NM_014000.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152078Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251406Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135864
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GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461782Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727192
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 17, 2015 | The c.622+4C>G variant in VCL has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 5/66734 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20 1020802). This variant is located in the 5' splice region. Computational tools d o not suggest an impact to splicing, though this information is not predictive e nough to rule out pathogenicity. In summary, the clinical significance of the c. 622+4C>G variant is uncertain. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Dilated cardiomyopathy 1W Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2023 | 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: 229632). This variant has not been reported in the literature in individuals affected with VCL-related conditions. This variant is present in population databases (rs201020802, gnomAD 0.009%). This sequence change falls in intron 5 of the VCL gene. It does not directly change the encoded amino acid sequence of the VCL protein. It affects a nucleotide within the consensus splice site. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2023 | The c.622+4C>G intronic variant results from a C to G substitution 4 nucleotides after coding exon 5 in the VCL gene. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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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