Genetic Variant NM_015164.4:c.61-18T>G (chr1-15716219-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015164.4(PLEKHM2):c.61-18T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,345,944 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.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 33)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.07

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
PLEKHM2	NM_015164.4 link	c.61-18T>G	intron_variant	Intron 1 of 19	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1 link	c.61-18T>G	intron_variant	Intron 1 of 18		NP_001397684.1
PLEKHM2	XM_017000757.1 link	c.100-18T>G	intron_variant	Intron 1 of 19		XP_016856246.1
PLEKHM2	XM_017000758.1 link	c.100-18T>G	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.61-18T>G	intron_variant	Intron 1 of 19	1	NM_015164.4	ENSP00000364956.3	Q8IWE5-1
PLEKHM2	ENST00000375793.2 link	c.61-18T>G	intron_variant	Intron 1 of 18	5		ENSP00000364950.2	Q8IWE5-2
PLEKHM2	ENST00000642363.1 link	c.61-18T>G	intron_variant	Intron 1 of 20			ENSP00000494591.1	A0A2R8Y575
PLEKHM2	ENST00000462455.1 link	n.79-18T>G	intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.00000691

AC:

AN:

144720

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000261

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:

8.32e-7

AC:

AN:

1201224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

603002

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000224

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000691

AC:

AN:

144720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70736

show subpopulations

Gnomad4 AFR

AF:

0.0000261

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

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

1.4

DANN

Benign

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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