1-15684611-TGAA-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_015164.4(PLEKHM2):c.58_60del(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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

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 AF: 0.00000668 AC: 1 AN: 149726 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000250 AC: 3 AN: 120074 Hom.: 0 AF XY: 0.0000435 AC XY: 3 AN XY: 69016

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000762

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000338

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000261 AC: 3 AN: 1151174 Hom.: 0 AF XY: 0.00000535 AC XY: 3 AN XY: 560518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000281

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000212

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149828 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 73172

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs745635006; hg19: chr1-16011106;