rs115985482

Positions:

• chr1-15719829-C-G
• chr1-15719829-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015164.4(PLEKHM2):​c.561C>G​(p.His187Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H187H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.91

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 (HGNC:):

ACMG classification

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=0.04059282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.561C>G	p.His187Gln	missense_variant	6/20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1	c.561C>G	p.His187Gln	missense_variant	6/19		NP_001397684.1
PLEKHM2	XM_017000757.1	c.600C>G	p.His200Gln	missense_variant	6/20		XP_016856246.1
PLEKHM2	XM_017000758.1	c.600C>G	p.His200Gln	missense_variant	6/19		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.561C>G	p.His187Gln	missense_variant	6/20	1	NM_015164.4	ENSP00000364956.3
PLEKHM2	ENST00000375793.2	c.561C>G	p.His187Gln	missense_variant	6/19	5		ENSP00000364950.2
PLEKHM2	ENST00000642363.1	c.561C>G	p.His187Gln	missense_variant	6/21			ENSP00000494591.1
PLEKHM2	ENST00000462455.1	n.469C>G		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249198 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461544 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.018
DANN	Benign	0.80
DEOGEN2	Benign	0.016	T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.13	T;T;.
Sift4G	Benign	0.34	T;T;.
Polyphen		0.0010	B;.;.
Vest4		0.21
MutPred		0.20		Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);
MVP		0.061
MPC		0.15
ClinPred		0.070	T
GERP RS		-11
Varity_R		0.060
gMVP		0.18

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: rs115985482; hg19: chr1-16046324;