rs749571694
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4
The NM_002667.5(PLN):c.34A>G(p.Ile12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. I12M) has been classified as Uncertain significance.
Frequency
Consequence
NM_002667.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLN | NM_002667.5 | c.34A>G | p.Ile12Val | missense_variant | 2/2 | ENST00000357525.6 | |
CEP85L | NM_001042475.3 | c.1020+6574T>C | intron_variant | ENST00000368491.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLN | ENST00000357525.6 | c.34A>G | p.Ile12Val | missense_variant | 2/2 | 1 | NM_002667.5 | P1 | |
CEP85L | ENST00000368491.8 | c.1020+6574T>C | intron_variant | 1 | NM_001042475.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251110Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135720
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461310Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17AN XY: 727022
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 09, 2016 | The I12V variant in the PLN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I12V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I12V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I12V as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 08, 2019 | - - |
Dilated cardiomyopathy 1P Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the PLN protein (p.Ile12Val). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 234806). This missense change has been observed in individual(s) with clinical features of cardiomyopathy or connective tissue disease (PMID: 30242101). This variant is present in population databases (rs749571694, gnomAD 0.02%). - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 02, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2021 | The p.I12V variant (also known as c.34A>G), located in coding exon 1 of the PLN gene, results from an A to G substitution at nucleotide position 34. The isoleucine at codon 12 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at