1-15684566-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.8C>A	p.Pro3Gln	missense_variant	Exon 1 of 20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1	c.8C>A	p.Pro3Gln	missense_variant	Exon 1 of 19		NP_001397684.1
PLEKHM2	XM_017000757.1	c.99+2867C>A		intron_variant	Intron 1 of 19		XP_016856246.1
PLEKHM2	XM_017000758.1	c.99+2867C>A		intron_variant	Intron 1 of 18		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.8C>A	p.Pro3Gln	missense_variant	Exon 1 of 20	1	NM_015164.4	ENSP00000364956.3
PLEKHM2	ENST00000375793.2	c.8C>A	p.Pro3Gln	missense_variant	Exon 1 of 19	5		ENSP00000364950.2
PLEKHM2	ENST00000642363.1	c.8C>A	p.Pro3Gln	missense_variant	Exon 1 of 21			ENSP00000494591.1
PLEKHM2	ENST00000462455.1	n.26C>A		non_coding_transcript_exon_variant	Exon 1 of 5	5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000269

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.25	N;N;.
REVEL	Benign	0.036
Sift	Benign	0.35	T;T;.
Sift4G	Benign	0.69	T;T;.
Polyphen		0.067	B;.;.
Vest4		0.28
MutPred		0.34		Loss of catalytic residue at P3 (P = 0.0611);Loss of catalytic residue at P3 (P = 0.0611);Loss of catalytic residue at P3 (P = 0.0611);
MVP		0.23
MPC		0.15
ClinPred		0.27	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.085

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: rs866837651; hg19: chr1-16011061;