rs200700186

Variant names:

• chr1-15730551-G-A
• rs200700186
• NM_015164.4:c.2228G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015164.4(PLEKHM2):​c.2228G>A​(p.Arg743His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,592,154 control chromosomes in the GnomAD database, including 5 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R743C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (4 hom.)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.82
• Publications: 2 publications found

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

ENSG00000237938 (HGNC:58402):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061187446).
• BP6: Variant 1-15730551-G-A is Benign according to our data. Variant chr1-15730551-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 478080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015164.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	NM_015164.4	MANE Select	c.2228G>A	p.Arg743His	missense	Exon 15 of 20	NP_055979.2
	PLEKHM2	NM_001410755.1		c.2168G>A	p.Arg723His	missense	Exon 14 of 19	NP_001397684.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.2228G>A	p.Arg743His	missense	Exon 15 of 20	ENSP00000364956.3
	PLEKHM2	ENST00000850891.1		c.2267G>A	p.Arg756His	missense	Exon 15 of 20	ENSP00000520968.1
	PLEKHM2	ENST00000375793.3	TSL:5	c.2168G>A	p.Arg723His	missense	Exon 14 of 19	ENSP00000364950.2

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152246 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00130 AC: 281 AN: 215780 AF XY: 0.00130

Gnomad AFR exome AF: 0.000320

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.000223

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000257

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.00186 AC: 2676 AN: 1439790 Hom.: 4 Cov.: 32 AF XY: 0.00184 AC XY: 1315 AN XY: 714076

African (AFR) AF: 0.000304 AC: 10 AN: 32910

American (AMR) AF: 0.00307 AC: 129 AN: 42080

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25384

East Asian (EAS) AF: 0.00 AC: 0 AN: 38548

South Asian (SAS) AF: 0.0000967 AC: 8 AN: 82706

European-Finnish (FIN) AF: 0.000137 AC: 7 AN: 51044

Middle Eastern (MID) AF: 0.00229 AC: 13 AN: 5666

European-Non Finnish (NFE) AF: 0.00215 AC: 2373 AN: 1101918

Other (OTH) AF: 0.00227 AC: 135 AN: 59534

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152364 Hom.: 1 Cov.: 33 AF XY: 0.00142 AC XY: 106 AN XY: 74512

African (AFR) AF: 0.000337 AC: 14 AN: 41584

American (AMR) AF: 0.00307 AC: 47 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10632

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00152 Hom.: 1

Bravo AF: 0.00200

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000482 AC: 2

ESP6500EA AF: 0.00107 AC: 9

ExAC AF: 0.00101 AC: 122

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

PLEKHM2-related disorder Benign:1

Apr 07, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PhyloP100		1.8
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.72	N
REVEL	Benign	0.022
Sift	Benign	0.63	T
Sift4G	Benign	0.39	T
Polyphen		0.0050	B
Vest4		0.20
MVP		0.25
MPC		0.19
ClinPred		0.0042	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.29
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs200700186; hg19: chr1-16057046;