Genetic Variant PLEKHM2:p.Ser17* (chr1-15684608-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_015164.4(PLEKHM2):c.50C>A(p.Ser17*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000861 in 1,161,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S17S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.70

Publications

0 publications found

Variant links:

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

PLEKHM2 links:

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ACMG classification

Classification was made for transcript

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	NM_015164.4	MANE Select	c.50C>A	p.Ser17*	stop_gained	Exon 1 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.50C>A	p.Ser17*	stop_gained	Exon 1 of 19	NP_001397684.1	Q8IWE5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.50C>A	p.Ser17*	stop_gained	Exon 1 of 20	ENSP00000364956.3	Q8IWE5-1
PLEKHM2	ENST00000957356.1		c.50C>A	p.Ser17*	stop_gained	Exon 1 of 21	ENSP00000627415.1
PLEKHM2	ENST00000957353.1		c.50C>A	p.Ser17*	stop_gained	Exon 1 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.61e-7

AC:

AN:

1161028

Hom.:

Cov.:

AF XY:

0.00000176

AC XY:

AN XY:

566584

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23964

American (AMR)

AF:

0.00

AC:

AN:

19884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16280

East Asian (EAS)

AF:

0.00

AC:

AN:

25574

South Asian (SAS)

AF:

0.0000268

AC:

AN:

37336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4452

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

950554

Other (OTH)

AF:

0.00

AC:

AN:

44304

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.26

PhyloP100

1.7

Vest4

0.064

GERP RS

1.9

PromoterAI

-0.082

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=4/196

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.45

Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over