rs202014397

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015164.4(PLEKHM2):c.1495G>T(p.Ala499Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000393 in 1,575,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.73

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: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics

PLEKHM2 links:

ENSG00000237938 (HGNC:58402):

ENSG00000237938 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026167661).

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.1495G>T	p.Ala499Ser	missense	Exon 9 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.1435G>T	p.Ala479Ser	missense	Exon 8 of 19	NP_001397684.1	Q8IWE5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.1495G>T	p.Ala499Ser	missense	Exon 9 of 20	ENSP00000364956.3	Q8IWE5-1
PLEKHM2	ENST00000957356.1		c.1603G>T	p.Ala535Ser	missense	Exon 10 of 21	ENSP00000627415.1
PLEKHM2	ENST00000957353.1		c.1495G>T	p.Ala499Ser	missense	Exon 9 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

151732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000654

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

187862

AF XY:

0.0000198

show subpopulations

Gnomad AFR exome

AF:

0.000581

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000232

AC:

AN:

1423928

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

705008

show subpopulations

African (AFR)

AF:

0.000889

AC:

AN:

32628

American (AMR)

AF:

0.0000261

AC:

AN:

38346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25460

East Asian (EAS)

AF:

0.00

AC:

AN:

37614

South Asian (SAS)

AF:

0.00

AC:

AN:

81554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093336

Other (OTH)

AF:

0.0000507

AC:

AN:

59138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000191

AC:

AN:

151732

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

74052

show subpopulations

African (AFR)

AF:

0.000654

AC:

AN:

41296

American (AMR)

AF:

0.000131

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67936

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000108

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.000999

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000334

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dilated Cardiomyopathy, Recessive (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.017

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.68

M_CAP

Benign

0.012

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

1.7

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.37

REVEL

Benign

0.037

Sift

Benign

0.19

Sift4G

Benign

0.78

Polyphen

0.055

Vest4

0.14

MVP

0.24

MPC

0.21

ClinPred

0.020

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.028

gMVP

0.13

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over