1-15733845-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015164.4(PLEKHM2):​c.2971T>C​(p.Phe991Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,612,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.27
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.059260726).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLEKHM2NM_015164.4 linkuse as main transcriptc.2971T>C p.Phe991Leu missense_variant 20/20 ENST00000375799.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLEKHM2ENST00000375799.8 linkuse as main transcriptc.2971T>C p.Phe991Leu missense_variant 20/201 NM_015164.4 P2Q8IWE5-1
ENST00000453804.1 linkuse as main transcriptn.37-1284A>G intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152072
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000507
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD3 exomes
AF:
0.0000402
AC:
10
AN:
248788
Hom.:
0
AF XY:
0.0000370
AC XY:
5
AN XY:
135126
show subpopulations
Gnomad AFR exome
AF:
0.000453
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1460784
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
726702
show subpopulations
Gnomad4 AFR exome
AF:
0.000448
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152190
Hom.:
0
Cov.:
33
AF XY:
0.000161
AC XY:
12
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.000626
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.000117
ESP6500AA
AF:
0.000965
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000413
AC:
5
Asia WGS
AF:
0.00144
AC:
5
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 submitterclinical testingInvitaeNov 13, 2023This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 991 of the PLEKHM2 protein (p.Phe991Leu). This variant is present in population databases (rs201091991, 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: 544340). 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. 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
Pathogenic
0.75
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
23
DANN
Benign
0.91
DEOGEN2
Benign
0.025
T;.;.
Eigen
Benign
0.0025
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.77
T;T;T
M_CAP
Benign
0.0064
T
MetaRNN
Benign
0.059
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
M;.;.
MutationTaster
Benign
0.99
D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.23
N;N;.
REVEL
Benign
0.12
Sift
Benign
0.85
T;T;.
Sift4G
Benign
0.19
T;T;.
Polyphen
0.0
B;.;.
Vest4
0.20
MutPred
0.41
Loss of methylation at K990 (P = 0.0299);.;.;
MVP
0.36
MPC
0.18
ClinPred
0.12
T
GERP RS
5.6
Varity_R
0.17
gMVP
0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201091991; hg19: chr1-16060340; COSMIC: COSV53816738; COSMIC: COSV53816738; API