PLEKHM2 p.Asn273Lys

Variant names:

• chr1-15725423-C-A
• NM_015164.4:c.819C>A
• PLEKHM2 p.Asn273Lys

Your query was ambiguous. Multiple possible variants found:

• chr1-15725423-C-A
• chr1-15725423-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015164.4(PLEKHM2):​c.819C>A​(p.Asn273Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N273N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 0 publications found

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]

PLEKHM2 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen

ENSG00000237938 (HGNC:58402):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09868407).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015164.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	NM_015164.4	MANE Select	c.819C>A	p.Asn273Lys	missense	Exon 8 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.759C>A	p.Asn253Lys	missense	Exon 7 of 19	NP_001397684.1	Q8IWE5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.819C>A	p.Asn273Lys	missense	Exon 8 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.927C>A	p.Asn309Lys	missense	Exon 9 of 21	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.819C>A	p.Asn273Lys	missense	Exon 8 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		-1.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.20	T
Varity_R		0.29
gMVP		0.32
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-16051918;