rs768068764
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_015164.4(PLEKHM2):c.2651G>A(p.Ser884Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,557,302 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 (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
PLEKHM2
NM_015164.4 missense
NM_015164.4 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 5.13
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2622078).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHM2 | NM_015164.4 | c.2651G>A | p.Ser884Asn | missense_variant | 18/20 | ENST00000375799.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHM2 | ENST00000375799.8 | c.2651G>A | p.Ser884Asn | missense_variant | 18/20 | 1 | NM_015164.4 | P2 | |
ENST00000453804.1 | n.211+12C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
4
AN:
152178
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.0000164 AC: 23AN: 1405124Hom.: 0 Cov.: 32 AF XY: 0.0000101 AC XY: 7AN XY: 693684
GnomAD4 exome
AF:
AC:
23
AN:
1405124
Hom.:
Cov.:
32
AF XY:
AC XY:
7
AN XY:
693684
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74352
GnomAD4 genome
?
AF:
AC:
4
AN:
152178
Hom.:
Cov.:
33
AF XY:
AC XY:
3
AN XY:
74352
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
?
AF:
AC:
1
Asia WGS
AF:
AC:
1
AN:
3478
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dilated Cardiomyopathy, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 14, 2023 | 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 567754). This variant has not been reported in the literature in individuals affected with PLEKHM2-related conditions. This variant is present in population databases (rs768068764, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 884 of the PLEKHM2 protein (p.Ser884Asn). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Benign
Sift
Benign
D;D;.
Sift4G
Uncertain
D;D;.
Polyphen
P;.;.
Vest4
MutPred
Loss of glycosylation at S884 (P = 0.029);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at