rs777617736
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_014000.3(VCL):c.874+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,613,252 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000035 ( 1 hom. )
Consequence
VCL
NM_014000.3 intron
NM_014000.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.890
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 -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 10-74082557-T-C is Benign according to our data. Variant chr10-74082557-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 517310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74082557-T-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000349 (51/1460944) while in subpopulation MID AF= 0.0033 (19/5764). AF 95% confidence interval is 0.00216. There are 1 homozygotes in gnomad4_exome. There are 27 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.874+13T>C | intron_variant | ENST00000211998.10 | |||
VCL | NM_003373.4 | c.874+13T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCL | ENST00000211998.10 | c.874+13T>C | intron_variant | 1 | NM_014000.3 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251016Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135670
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GnomAD4 exome AF: 0.0000349 AC: 51AN: 1460944Hom.: 1 Cov.: 31 AF XY: 0.0000371 AC XY: 27AN XY: 726820
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74486
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2017 | c.874+13T>C in intron 7 of VCL: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence. It h as been identified in 3/11416 Latino chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs777617736). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2021 | Variant summary: VCL c.874+13T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 251016 control chromosomes. The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant may be benign. To our knowledge, no occurrence of c.874+13T>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Dilated cardiomyopathy 1W Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
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DANN
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Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at