rs751230545

Positions:

chr1-15719899-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_015164.4(PLEKHM2):c.631G>A(p.Ala211Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,298 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A211V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.69

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 links:

PLEKHM2 (HGNC:):

PLEKHM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3532573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PLEKHM2	NM_015164.4 linkuse as main transcript	c.631G>A	p.Ala211Thr	missense_variant	6/20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1 linkuse as main transcript	c.631G>A	p.Ala211Thr	missense_variant	6/19		NP_001397684.1
PLEKHM2	XM_017000757.1 linkuse as main transcript	c.670G>A	p.Ala224Thr	missense_variant	6/20		XP_016856246.1
PLEKHM2	XM_017000758.1 linkuse as main transcript	c.670G>A	p.Ala224Thr	missense_variant	6/19		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PLEKHM2	ENST00000375799.8 linkuse as main transcript	c.631G>A	p.Ala211Thr	missense_variant	6/20	1	NM_015164.4	ENSP00000364956.3	Q8IWE5-1
PLEKHM2	ENST00000375793.2 linkuse as main transcript	c.631G>A	p.Ala211Thr	missense_variant	6/19	5		ENSP00000364950.2	Q8IWE5-2
PLEKHM2	ENST00000642363.1 linkuse as main transcript	c.631G>A	p.Ala211Thr	missense_variant	6/21			ENSP00000494591.1	A0A2R8Y575
PLEKHM2	ENST00000462455.1 linkuse as main transcript	n.*30G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248128

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134622

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461170

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726822

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000324

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000103

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 211 of the PLEKHM2 protein (p.Ala211Thr). This variant is present in population databases (rs751230545, gnomAD 0.004%). 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: 478104). 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 disruptive. 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

0.90

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

T;.;.

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.1

M;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.3

N;N;.

REVEL

Benign

0.20

Sift

Uncertain

0.0050

D;D;.

Sift4G

Benign

0.095

T;T;.

Polyphen

0.99

D;.;.

Vest4

0.70

MutPred

0.20

Gain of glycosylation at A211 (P = 0.0059);Gain of glycosylation at A211 (P = 0.0059);Gain of glycosylation at A211 (P = 0.0059);

MVP

0.68

MPC

0.38

ClinPred

0.67

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over