rs200683247
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_020376.4(PNPLA2):āc.326A>Gā(p.His109Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_020376.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PNPLA2 | NM_020376.4 | c.326A>G | p.His109Arg | missense_variant | 3/10 | ENST00000336615.9 | NP_065109.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PNPLA2 | ENST00000336615.9 | c.326A>G | p.His109Arg | missense_variant | 3/10 | 1 | NM_020376.4 | ENSP00000337701.4 | ||
PNPLA2 | ENST00000525250.5 | n.932A>G | non_coding_transcript_exon_variant | 1/6 | 2 | |||||
PNPLA2 | ENST00000534561.1 | n.-8A>G | upstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251320Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135890
GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461664Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37AN XY: 727128
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74358
ClinVar
Submissions by phenotype
Neutral lipid storage myopathy Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 08, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 02, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2023 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 109 of the PNPLA2 protein (p.His109Arg). This variant is present in population databases (rs200683247, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with PNPLA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 306294). 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. - |
Likely benign, criteria provided, single submitter | clinical testing | 3billion | Sep 20, 2024 | The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at