chr1-15684611-TGAA-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_015164.4(PLEKHM2):βc.58_60delβ(p.Lys20del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000307 in 1,301,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β ).
Frequency
Genomes: π 0.0000067 ( 0 hom., cov: 30)
Exomes π: 0.0000026 ( 0 hom. )
Consequence
PLEKHM2
NM_015164.4 inframe_deletion
NM_015164.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.981
Genes affected
PLEKHM2 (HGNC:29131): (pleckstrin homology and RUN domain containing M2) This gene encodes a protein that binds the plus-end directed microtubule motor protein kinesin, together with the lysosomal GTPase Arl8, and is required for lysosomes to distribute away from the microtubule-organizing center. The encoded protein belongs to the multisubunit BLOC-one-related complex that regulates lysosome positioning. It binds a Salmonella effector protein called Salmonella induced filament A and is a critical host determinant in Salmonella pathogenesis. It has a domain architecture consisting of an N-terminal RPIP8, UNC-14, and NESCA (RUN) domain that binds kinesin-1 as well as the lysosomal GTPase Arl8, and a C-terminal pleckstrin homology domain that binds the Salmonella induced filament A effector protein. Naturally occurring mutations in this gene lead to abnormal localization of lysosomes, impaired autophagy flux and are associated with recessive dilated cardiomyopathy and left ventricular noncompaction. [provided by RefSeq, Feb 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_015164.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PLEKHM2 | NM_015164.4 | c.58_60del | p.Lys20del | inframe_deletion | 1/20 | ENST00000375799.8 | |
| PLEKHM2 | NM_001410755.1 | c.58_60del | p.Lys20del | inframe_deletion | 1/19 | ||
| PLEKHM2 | XM_017000757.1 | c.99+2917_99+2919del | intron_variant | ||||
| PLEKHM2 | XM_017000758.1 | c.99+2917_99+2919del | intron_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PLEKHM2 | ENST00000375799.8 | c.58_60del | p.Lys20del | inframe_deletion | 1/20 | 1 | NM_015164.4 | P2 | |
| PLEKHM2 | ENST00000375793.2 | c.58_60del | p.Lys20del | inframe_deletion | 1/19 | 5 | A2 | ||
| PLEKHM2 | ENST00000642363.1 | c.58_60del | p.Lys20del | inframe_deletion | 1/21 | A2 | |||
| PLEKHM2 | ENST00000462455.1 | n.76_78del | non_coding_transcript_exon_variant | 1/5 | 5 |
Frequencies
GnomAD3 genomes 0.00000668 AC: 1AN: 149726Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000250 AC: 3AN: 120074Hom.: 0 AF XY: 0.0000435 AC XY: 3AN XY: 69016
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GnomAD4 exome AF: 0.00000261 AC: 3AN: 1151174Hom.: 0 AF XY: 0.00000535 AC XY: 3AN XY: 560518
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GnomAD4 genome 0.00000667 AC: 1AN: 149828Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 73172
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dilated Cardiomyopathy, Recessive Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 23, 2022 | 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 disrupt the consensus splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with PLEKHM2-related conditions. This variant is present in population databases (rs745635006, gnomAD 0.008%). This variant, c.58_60del, results in the deletion of 1 amino acid(s) of the PLEKHM2 protein (p.Lys20del), but otherwise preserves the integrity of the reading frame. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at