chr1-15732010-G-A

Variant names:

• chr1-15732010-G-A
• rs1412158115
• NM_015164.4:c.2587G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015164.4(PLEKHM2):​c.2587G>A​(p.Glu863Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48
• Publications: 0 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: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics

ENSG00000237938 (HGNC:58402):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	NM_015164.4	MANE Select	c.2587G>A	p.Glu863Lys	missense	Exon 17 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.2527G>A	p.Glu843Lys	missense	Exon 16 of 19	NP_001397684.1	Q8IWE5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.2587G>A	p.Glu863Lys	missense	Exon 17 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.2695G>A	p.Glu899Lys	missense	Exon 18 of 21	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.2632G>A	p.Glu878Lys	missense	Exon 17 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000811 AC: 2 AN: 246614 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000616 AC: 9 AN: 1460102 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726328

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111646

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated Cardiomyopathy, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.90	L
PhyloP100		7.5
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.43
Sift	Benign	0.20	T
Sift4G	Uncertain	0.015	D
Polyphen		0.63	P
Vest4		0.51
MVP		0.73
MPC		0.17
ClinPred		0.45	T
GERP RS		5.1
Varity_R		0.24
gMVP		0.43
Mutation Taster		=80/20	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: rs1412158115; hg19: chr1-16058505;