Genetic Variant PLEKHM2:p.Ala211Glu (chr1-15719900-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_015164.4(PLEKHM2):c.632C>A(p.Ala211Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A211V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.66

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PLEKHM2	NM_015164.4 link	c.632C>A	p.Ala211Glu	missense_variant	Exon 6 of 20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1 link	c.632C>A	p.Ala211Glu	missense_variant	Exon 6 of 19		NP_001397684.1
PLEKHM2	XM_017000757.1 link	c.671C>A	p.Ala224Glu	missense_variant	Exon 6 of 20		XP_016856246.1
PLEKHM2	XM_017000758.1 link	c.671C>A	p.Ala224Glu	missense_variant	Exon 6 of 19		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8 link	c.632C>A	p.Ala211Glu	missense_variant	Exon 6 of 20	1	NM_015164.4	ENSP00000364956.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726636

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111368

Other (OTH)

AF:

0.00

AC:

AN:

60336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

T;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.49

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.1

M;.;.

PhyloP100

7.7

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.2

N;N;.

REVEL

Benign

0.29

Sift

Uncertain

0.0020

D;D;.

Sift4G

Benign

0.10

T;D;.

Polyphen

1.0

D;.;.

Vest4

0.77

MutPred

0.20

Gain of solvent accessibility (P = 0.0261);Gain of solvent accessibility (P = 0.0261);Gain of solvent accessibility (P = 0.0261);

MVP

0.67

MPC

0.57

ClinPred

0.91

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.79

Mutation Taster

=40/60

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over