rs758811315
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_014000.3(VCL):c.1247G>A(p.Arg416Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R416W) has been classified as Uncertain significance.
Frequency
Consequence
NM_014000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.1247G>A | p.Arg416Gln | missense_variant | 10/22 | ENST00000211998.10 | |
VCL | NM_003373.4 | c.1247G>A | p.Arg416Gln | missense_variant | 10/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCL | ENST00000211998.10 | c.1247G>A | p.Arg416Gln | missense_variant | 10/22 | 1 | NM_014000.3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251404Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135866
GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727234
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74308
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1W Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 416 of the VCL protein (p.Arg416Gln). This variant is present in population databases (rs758811315, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 408950). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 408950; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2023 | The c.1247G>A (p.R416Q) alteration is located in exon 10 (coding exon 10) of the VCL gene. This alteration results from a G to A substitution at nucleotide position 1247, causing the arginine (R) at amino acid position 416 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at