NM_015164.4:c.2823C>G

Variant summary

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

The NM_015164.4(PLEKHM2):​c.2823C>G​(p.Ser941Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,603,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: 0.635

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

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=0.021284014).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLEKHM2NM_015164.4 linkc.2823C>G p.Ser941Arg missense_variant Exon 19 of 20 ENST00000375799.8 NP_055979.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLEKHM2ENST00000375799.8 linkc.2823C>G p.Ser941Arg missense_variant Exon 19 of 20 1 NM_015164.4 ENSP00000364956.3 Q8IWE5-1

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152142
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00151
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:
0.000956
GnomAD2 exomes
AF:
0.0000130
AC:
3
AN:
231444
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000307
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:
0.000349
GnomAD4 exome
AF:
0.00000620
AC:
9
AN:
1451620
Hom.:
0
Cov.:
32
AF XY:
0.00000555
AC XY:
4
AN XY:
721246
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33300
American (AMR)
AF:
0.000162
AC:
7
AN:
43216
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25806
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39352
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84640
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52108
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5754
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1107404
Other (OTH)
AF:
0.0000333
AC:
2
AN:
60040
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000197
AC:
30
AN:
152142
Hom.:
0
Cov.:
33
AF XY:
0.000242
AC XY:
18
AN XY:
74320
show subpopulations
African (AFR)
AF:
0.000121
AC:
5
AN:
41420
American (AMR)
AF:
0.00151
AC:
23
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68004
Other (OTH)
AF:
0.000956
AC:
2
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000451
Hom.:
0
Bravo
AF:
0.000397
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 15, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2823C>G (p.S941R) alteration is located in exon 19 (coding exon 19) of the PLEKHM2 gene. This alteration results from a C to G substitution at nucleotide position 2823, causing the serine (S) at amino acid position 941 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dilated Cardiomyopathy, Recessive Uncertain:1
Dec 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 941 of the PLEKHM2 protein (p.Ser941Arg). This variant is present in population databases (rs749682801, gnomAD 0.003%). 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: 544341). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
Benign
0.18
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
19
DANN
Benign
0.71
DEOGEN2
Benign
0.011
T;.;.
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.60
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.021
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.090
N;.;.
PhyloP100
0.64
PrimateAI
Benign
0.31
T
PROVEAN
Benign
0.090
N;N;.
REVEL
Benign
0.033
Sift
Benign
0.69
T;T;.
Sift4G
Benign
1.0
T;T;.
Polyphen
0.0
B;.;.
Vest4
0.21
MutPred
0.28
Gain of helix (P = 0.0325);.;.;
MVP
0.23
MPC
0.17
ClinPred
0.033
T
GERP RS
3.3
Varity_R
0.10
gMVP
0.51
Mutation Taster
=91/9
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs749682801; hg19: chr1-16059124; API