NM_015164.4:c.51G>A

Variant names:

• chr1-15684609-G-A
• rs370753597
• NM_015164.4:c.51G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_015164.4(PLEKHM2):​c.51G>A​(p.Ser17Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,303,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0360
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-15684609-G-A is Benign according to our data. Variant chr1-15684609-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 772520.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.036 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.51G>A	p.Ser17Ser	synonymous	Exon 1 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.51G>A	p.Ser17Ser	synonymous	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.51G>A	p.Ser17Ser	synonymous	Exon 1 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.51G>A	p.Ser17Ser	synonymous	Exon 1 of 21	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.51G>A	p.Ser17Ser	synonymous	Exon 1 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes AF: 0.0000665 AC: 10 AN: 150372 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000333 AC: 4 AN: 120096 AF XY: 0.0000580

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000148

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000508

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 167 AN: 1152744 Hom.: 0 Cov.: 29 AF XY: 0.000144 AC XY: 81 AN XY: 561272

African (AFR) AF: 0.00 AC: 0 AN: 23806

American (AMR) AF: 0.00 AC: 0 AN: 19092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15872

East Asian (EAS) AF: 0.0000391 AC: 1 AN: 25572

South Asian (SAS) AF: 0.00 AC: 0 AN: 35502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4388

European-Non Finnish (NFE) AF: 0.000170 AC: 161 AN: 946172

Other (OTH) AF: 0.000114 AC: 5 AN: 44012

GnomAD4 genome AF: 0.0000665 AC: 10 AN: 150372 Hom.: 0 Cov.: 30 AF XY: 0.0000409 AC XY: 3 AN XY: 73430

African (AFR) AF: 0.00 AC: 0 AN: 41130

American (AMR) AF: 0.00 AC: 0 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67442

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated Cardiomyopathy, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Uncertain	0.99
PhyloP100		0.036
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs370753597; hg19: chr1-16011104;