NM_015164.4:c.131G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_015164.4(PLEKHM2):c.131G>A(p.Arg44His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000728 in 1,606,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.91

Publications

0 publications found

Variant links:

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: LIMITED Submitted by: ClinGen, Ambry Genetics

PLEKHM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38094485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PLEKHM2	NM_015164.4 link	c.131G>A	p.Arg44His	missense_variant	Exon 2 of 20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1 link	c.131G>A	p.Arg44His	missense_variant	Exon 2 of 19		NP_001397684.1
PLEKHM2	XM_017000757.1 link	c.170G>A	p.Arg57His	missense_variant	Exon 2 of 20		XP_016856246.1
PLEKHM2	XM_017000758.1 link	c.170G>A	p.Arg57His	missense_variant	Exon 2 of 19		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8 link	c.131G>A	p.Arg44His	missense_variant	Exon 2 of 20	1	NM_015164.4	ENSP00000364956.3		Q8IWE5-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000101

AC:

AN:

237232

AF XY:

0.0000857

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000511

Gnomad EAS exome

AF:

0.0000576

Gnomad FIN exome

AF:

0.0000488

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000743

AC:

108

AN:

1454246

Hom.:

Cov.:

AF XY:

0.0000692

AC XY:

AN XY:

722526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

43760

Ashkenazi Jewish (ASJ)

AF:

0.000269

AC:

AN:

25984

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39540

South Asian (SAS)

AF:

0.0000472

AC:

AN:

84736

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000821

AC:

AN:

1108294

Other (OTH)

AF:

0.0000665

AC:

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000592

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000950

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dilated Cardiomyopathy, Recessive

Uncertain:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 44 of the PLEKHM2 protein (p.Arg44His). This variant is present in population databases (rs750819902, 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: 478068). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.031

T;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.1

M;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.9

N;N;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.010

D;D;.

Sift4G

Uncertain

0.0090

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.82

MVP

0.45

MPC

0.73

ClinPred

0.47

GERP RS

6.1

Varity_R

0.27

gMVP

0.42

Mutation Taster

=64/36

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over