rs201860640

Variant names:

• chr1-15718592-C-A
• rs201860640
• NM_015164.4:c.432C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-15718592-C-A
• chr1-15718592-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.432C>A​(p.Ser144Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000798 in 1,253,118 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. S144S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69
• 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

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=-0.47).
• BP7: Synonymous conserved (PhyloP=-2.69 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	NM_015164.4	MANE Select	c.432C>A	p.Ser144Ser	synonymous	Exon 5 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.432C>A	p.Ser144Ser	synonymous	Exon 5 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.432C>A	p.Ser144Ser	synonymous	Exon 5 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.432C>A	p.Ser144Ser	synonymous	Exon 5 of 21	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.432C>A	p.Ser144Ser	synonymous	Exon 5 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.98e-7 AC: 1 AN: 1253118 Hom.: 0 Cov.: 31 AF XY: 0.00000162 AC XY: 1 AN XY: 618370

African (AFR) AF: 0.00 AC: 0 AN: 27532

American (AMR) AF: 0.00 AC: 0 AN: 34696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18946

East Asian (EAS) AF: 0.00 AC: 0 AN: 20962

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4772

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 981822

Other (OTH) AF: 0.00 AC: 0 AN: 47494

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.5
DANN	Benign	0.83
PhyloP100		-2.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201860640; hg19: chr1-16045087;