11-822437-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_020376.4(PNPLA2):āc.527A>Gā(p.Tyr176Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. Y176Y) has been classified as Likely benign.
Frequency
Consequence
NM_020376.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNPLA2 | NM_020376.4 | c.527A>G | p.Tyr176Cys | missense_variant | 5/10 | ENST00000336615.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNPLA2 | ENST00000336615.9 | c.527A>G | p.Tyr176Cys | missense_variant | 5/10 | 1 | NM_020376.4 | P1 | |
PNPLA2 | ENST00000525250.5 | n.1133A>G | non_coding_transcript_exon_variant | 3/6 | 2 | ||||
PNPLA2 | ENST00000531923.1 | n.422A>G | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251438Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461784Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727196
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Neutral lipid storage myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2021 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). This variant has not been reported in the literature in individuals affected with PNPLA2-related conditions. This variant is present in population databases (rs141014055, ExAC 0.002%). This sequence change replaces tyrosine with cysteine at codon 176 of the PNPLA2 protein (p.Tyr176Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 26, 2023 | The c.527A>G (p.Y176C) alteration is located in exon 5 (coding exon 4) of the PNPLA2 gene. This alteration results from a A to G substitution at nucleotide position 527, causing the tyrosine (Y) at amino acid position 176 to be replaced by a cysteine (C). 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