10-74101048-T-C
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_014000.3(VCL):āc.1973T>Cā(p.Val658Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,613,824 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V658M) has been classified as Uncertain significance.
Frequency
Consequence
NM_014000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.1973T>C | p.Val658Ala | missense_variant | 14/22 | ENST00000211998.10 | |
VCL | NM_003373.4 | c.1973T>C | p.Val658Ala | missense_variant | 14/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCL | ENST00000211998.10 | c.1973T>C | p.Val658Ala | missense_variant | 14/22 | 1 | NM_014000.3 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152094Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000359 AC: 90AN: 250940Hom.: 2 AF XY: 0.000509 AC XY: 69AN XY: 135648
GnomAD4 exome AF: 0.000185 AC: 270AN: 1461612Hom.: 2 Cov.: 31 AF XY: 0.000263 AC XY: 191AN XY: 727108
GnomAD4 genome AF: 0.0000985 AC: 15AN: 152212Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74432
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2014 | The Val658Ala variant in VCL has not been previously reported in individuals wit h cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical s ignificance of the variant. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Genetics and Genomics Program, Sidra Medicine | - | - - |
Dilated cardiomyopathy 1W Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2018 | This variant is associated with the following publications: (PMID: 26191084) - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 20, 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at