NM_015164.4:c.8C>A

Variant names:

• chr1-15684566-C-A
• rs866837651
• NM_015164.4:c.8C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015164.4(PLEKHM2):​c.8C>A​(p.Pro3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000877 in 1,140,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.364
• 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: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.117649734).

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.8C>A	p.Pro3Gln	missense	Exon 1 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.8C>A	p.Pro3Gln	missense	Exon 1 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.8C>A	p.Pro3Gln	missense	Exon 1 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.8C>A	p.Pro3Gln	missense	Exon 1 of 21	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.8C>A	p.Pro3Gln	missense	Exon 1 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 8.77e-7 AC: 1 AN: 1140742 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 555524

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23412

American (AMR) AF: 0.00 AC: 0 AN: 19650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15814

East Asian (EAS) AF: 0.00 AC: 0 AN: 23688

South Asian (SAS) AF: 0.0000269 AC: 1 AN: 37228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4270

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 936780

Other (OTH) AF: 0.00 AC: 0 AN: 42926

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.000413 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.36
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.25	N
REVEL	Benign	0.036
Sift	Benign	0.35	T
Sift4G	Benign	0.69	T
Polyphen		0.067	B
Vest4		0.28
MutPred		0.34		Loss of catalytic residue at P3 (P = 0.0611)
MVP		0.23
MPC		0.15
ClinPred		0.27	T
GERP RS		2.7
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.085
Mutation Taster		=94/6	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: rs866837651; hg19: chr1-16011061;