rs375845025
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_015164.4(PLEKHM2):āc.1738A>Gā(p.Met580Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,591,144 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M580T) has been classified as Uncertain significance.
Frequency
Consequence
NM_015164.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHM2 | NM_015164.4 | c.1738A>G | p.Met580Val | missense_variant | 9/20 | ENST00000375799.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHM2 | ENST00000375799.8 | c.1738A>G | p.Met580Val | missense_variant | 9/20 | 1 | NM_015164.4 | P2 | |
ENST00000453804.1 | n.212-4523T>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152072Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000235 AC: 5AN: 212342Hom.: 0 AF XY: 0.0000173 AC XY: 2AN XY: 115802
GnomAD4 exome AF: 0.0000264 AC: 38AN: 1439072Hom.: 0 Cov.: 33 AF XY: 0.0000294 AC XY: 21AN XY: 713084
GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152072Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7AN XY: 74252
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 01, 2021 | The c.1738A>G (p.M580V) alteration is located in exon 9 (coding exon 9) of the PLEKHM2 gene. This alteration results from a A to G substitution at nucleotide position 1738, causing the methionine (M) at amino acid position 580 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Dilated Cardiomyopathy, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 580 of the PLEKHM2 protein (p.Met580Val). This variant is present in population databases (rs375845025, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PLEKHM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 576149). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at