rs376306853

Variant names:

• chr1-15727337-A-C
• rs376306853
• NM_015164.4:c.1265A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-15727337-A-C
• chr1-15727337-A-G

Variant summary

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

The NM_015164.4(PLEKHM2):​c.1265A>C​(p.Asp422Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D422G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.68
• 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	NM_015164.4	MANE Select	c.1265A>C	p.Asp422Ala	missense	Exon 9 of 20	NP_055979.2
	PLEKHM2	NM_001410755.1		c.1205A>C	p.Asp402Ala	missense	Exon 8 of 19	NP_001397684.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.1265A>C	p.Asp422Ala	missense	Exon 9 of 20	ENSP00000364956.3
	PLEKHM2	ENST00000850891.1		c.1304A>C	p.Asp435Ala	missense	Exon 9 of 20	ENSP00000520968.1
	PLEKHM2	ENST00000375793.3	TSL:5	c.1205A>C	p.Asp402Ala	missense	Exon 8 of 19	ENSP00000364950.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.038	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.38		Gain of helix (P = 0.005)
MVP		0.60
MPC		0.73
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.56
gMVP		0.51
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs376306853; hg19: chr1-16053832;