Genetic Variant PLEKHM2:c.60+80_60+81insCGACCCTGCTACCGCAGGGACTCG (chr1-15684697-G-GGCGACCCTGCTACCGCAGGGACTC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015164.4(PLEKHM2):c.60+80_60+81insCGACCCTGCTACCGCAGGGACTCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 795,264 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
PLEKHM2	NM_015164.4 link	c.60+80_60+81insCGACCCTGCTACCGCAGGGACTCG	intron_variant	Intron 1 of 19	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1 link	c.60+80_60+81insCGACCCTGCTACCGCAGGGACTCG	intron_variant	Intron 1 of 18		NP_001397684.1
PLEKHM2	XM_017000757.1 link	c.99+2999_99+3000insCGACCCTGCTACCGCAGGGACTCG	intron_variant	Intron 1 of 19		XP_016856246.1
PLEKHM2	XM_017000758.1 link	c.99+2999_99+3000insCGACCCTGCTACCGCAGGGACTCG	intron_variant	Intron 1 of 18		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLEKHM2	ENST00000375799.8 link	c.60+79_60+80insGCGACCCTGCTACCGCAGGGACTC	intron_variant	Intron 1 of 19	1	NM_015164.4	ENSP00000364956.3	Q8IWE5-1
PLEKHM2	ENST00000375793.2 link	c.60+79_60+80insGCGACCCTGCTACCGCAGGGACTC	intron_variant	Intron 1 of 18	5		ENSP00000364950.2	Q8IWE5-2
PLEKHM2	ENST00000642363.1 link	c.60+79_60+80insGCGACCCTGCTACCGCAGGGACTC	intron_variant	Intron 1 of 20			ENSP00000494591.1	A0A2R8Y575
PLEKHM2	ENST00000462455.1 link	n.78+79_78+80insGCGACCCTGCTACCGCAGGGACTC	intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0000333

AC:

AN:

150316

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000620

AC:

AN:

644948

Hom.:

AF XY:

0.00000973

AC XY:

AN XY:

308400

show subpopulations

Gnomad4 AFR exome

AF:

0.000229

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000186

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000333

AC:

AN:

150316

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73320

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over