rs200700186

chr1-15730551-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

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. 15/21 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:2
• Conservation: PhyloP100: 1.82

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 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 id is 478080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM2	NM_015164.4	c.2228G>A	p.Arg743His	missense_variant	15/20	ENST00000375799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.2228G>A	p.Arg743His	missense_variant	15/20	1	NM_015164.4	P2
	ENST00000453804.1	n.211+1836C>T		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.00130 AC: 281 AN: 215780 Hom.: 0 AF XY: 0.00130 AC XY: 152 AN XY: 117274

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 SAS exome AF: 0.000187

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

Gnomad4 AFR exome AF: 0.000304

Gnomad4 AMR exome AF: 0.00307

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000967

Gnomad4 FIN exome AF: 0.000137

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00227

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

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00155 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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

PLEKHM2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2021

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 v4.3

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;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N;.;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.72	N;N;.
REVEL	Benign	0.022
Sift	Benign	0.63	T;T;.
Sift4G	Benign	0.39	T;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

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

Other links and lift over

dbSNP: rs200700186; hg19: chr1-16057046;