10-74097248-A-C
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The ENST00000211998.10(VCL):āc.1788A>Cā(p.Ser596=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,614,040 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 Likely benign (ā ā ).
Frequency
Genomes: š 0.00018 ( 0 hom., cov: 32)
Exomes š: 0.00015 ( 0 hom. )
Consequence
VCL
ENST00000211998.10 synonymous
ENST00000211998.10 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.298
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 -17 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 10-74097248-A-C is Benign according to our data. Variant chr10-74097248-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 45589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74097248-A-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.298 with no splicing effect.
BS2
High AC in GnomAd4 at 28 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.1788A>C | p.Ser596= | synonymous_variant | 13/22 | ENST00000211998.10 | NP_054706.1 | |
VCL | NM_003373.4 | c.1788A>C | p.Ser596= | synonymous_variant | 13/21 | NP_003364.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VCL | ENST00000211998.10 | c.1788A>C | p.Ser596= | synonymous_variant | 13/22 | 1 | NM_014000.3 | ENSP00000211998 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152236Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000175 AC: 44AN: 251454Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135898
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GnomAD4 exome AF: 0.000154 AC: 225AN: 1461804Hom.: 0 Cov.: 31 AF XY: 0.000158 AC XY: 115AN XY: 727204
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GnomAD4 genome AF: 0.000184 AC: 28AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74382
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
VCL-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 05, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 14, 2010 | - - |
Dilated cardiomyopathy 1W Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2017 | Variant summary: The c.1788A>C (p.Ser596=) in VCL gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not have a major effect on a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in control population dataset of ExAC at a frequency of 0.0001648 (20/121354 chrs tested). This frequency exceeds the estimated maximal expected allele frequency of a pathogenic variant in VCL gene (0.000025). The variant has not been reported in affected individuals, but is cited as Likely Benign by a reputable database/diagnostic center. Taking together, the variant was classified as Benign. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 18, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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BayesDel_noAF
Benign
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DANN
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RBP_binding_hub_radar
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at