rs749126712

Variant names:

• chr1-15727323-C-A
• rs749126712
• NM_015164.4:c.1251C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-15727323-C-A
• chr1-15727323-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_015164.4(PLEKHM2):​c.1251C>A​(p.Leu417Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. L417L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.152
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=-0.152 with no splicing effect.

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.1251C>A	p.Leu417Leu	synonymous	Exon 9 of 20	NP_055979.2
	PLEKHM2	NM_001410755.1		c.1191C>A	p.Leu397Leu	synonymous	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.1251C>A	p.Leu417Leu	synonymous	Exon 9 of 20	ENSP00000364956.3
	PLEKHM2	ENST00000850891.1		c.1290C>A	p.Leu430Leu	synonymous	Exon 9 of 20	ENSP00000520968.1
	PLEKHM2	ENST00000375793.3	TSL:5	c.1191C>A	p.Leu397Leu	synonymous	Exon 8 of 19	ENSP00000364950.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446906 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 718552

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.00 AC: 0 AN: 42768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39006

South Asian (SAS) AF: 0.00 AC: 0 AN: 83978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105732

Other (OTH) AF: 0.00 AC: 0 AN: 59786

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.8
DANN	Benign	0.77
PhyloP100		-0.15
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs749126712; hg19: chr1-16053818;