11-822565-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_020376.4(PNPLA2):c.655C>T(p.Leu219Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_020376.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PNPLA2 | ENST00000336615.9 | c.655C>T | p.Leu219Phe | missense_variant | Exon 5 of 10 | 1 | NM_020376.4 | ENSP00000337701.4 | ||
PNPLA2 | ENST00000525250.5 | n.1261C>T | non_coding_transcript_exon_variant | Exon 3 of 6 | 2 | |||||
PNPLA2 | ENST00000531923.1 | n.550C>T | non_coding_transcript_exon_variant | Exon 1 of 2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251194Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135842
GnomAD4 exome AF: 0.000237 AC: 347AN: 1461608Hom.: 0 Cov.: 32 AF XY: 0.000239 AC XY: 174AN XY: 727120
GnomAD4 genome AF: 0.000118 AC: 18AN: 152352Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74506
ClinVar
Submissions by phenotype
Neutral lipid storage myopathy Uncertain:3
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 219 of the PNPLA2 protein (p.Leu219Phe). This variant is present in population databases (rs140612115, gnomAD 0.02%). This missense change has been observed in individual(s) with obesity (PMID: 16644682). ClinVar contains an entry for this variant (Variation ID: 574730). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PNPLA2 protein function. 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. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at