chr1-15733848-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015164.4(PLEKHM2):ā€‹c.2974G>Cā€‹(p.Glu992Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. E992K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.000011 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.26
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 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=0.15950334).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLEKHM2NM_015164.4 linkuse as main transcriptc.2974G>C p.Glu992Gln missense_variant 20/20 ENST00000375799.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLEKHM2ENST00000375799.8 linkuse as main transcriptc.2974G>C p.Glu992Gln missense_variant 20/201 NM_015164.4 P2Q8IWE5-1
ENST00000453804.1 linkuse as main transcriptn.37-1287C>G intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1460794
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
726704
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.015
T;.;.
Eigen
Benign
-0.13
Eigen_PC
Benign
0.043
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Benign
0.0078
T
MetaRNN
Benign
0.16
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.8
L;.;.
MutationTaster
Benign
0.68
D;D
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-0.30
N;N;.
REVEL
Benign
0.048
Sift
Benign
0.14
T;T;.
Sift4G
Benign
0.25
T;T;.
Polyphen
0.15
B;.;.
Vest4
0.21
MutPred
0.14
Gain of MoRF binding (P = 0.0432);.;.;
MVP
0.43
MPC
0.33
ClinPred
0.68
D
GERP RS
4.7
Varity_R
0.15
gMVP
0.24

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: rs369250576; hg19: chr1-16060343; API