rs116455686

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_015164.4(PLEKHM2):c.2211A>G(p.Ala737=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00993 in 1,577,064 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0075 ( 7 hom., cov: 33)

Exomes 𝑓: 0.010 ( 101 hom. )

Consequence

PLEKHM2
NM_015164.4 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.98

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 1-15730534-A-G is Benign according to our data. Variant chr1-15730534-A-G is described in ClinVar as [Benign]. Clinvar id is 478078.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.98 with no splicing effect.

BS2

High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM2	NM_015164.4 linkuse as main transcript	c.2211A>G	p.Ala737=	splice_region_variant, synonymous_variant	15/20	ENST00000375799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM2	ENST00000375799.8 linkuse as main transcript	c.2211A>G	p.Ala737=	splice_region_variant, synonymous_variant	15/20	1	NM_015164.4	P2	Q8IWE5-1
	ENST00000453804.1 linkuse as main transcript	n.211+1853T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00750

AC:

1141

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00477

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00745

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00808

AC:

1616

AN:

200000

Hom.:

AF XY:

0.00852

AC XY:

923

AN XY:

108386

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.00332

Gnomad ASJ exome

AF:

0.0205

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00743

Gnomad FIN exome

AF:

0.00757

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0102

AC:

14517

AN:

1424740

Hom.:

101

Cov.:

AF XY:

0.0101

AC XY:

7151

AN XY:

705102

show subpopulations

Gnomad4 AFR exome

AF:

0.00132

Gnomad4 AMR exome

AF:

0.00364

Gnomad4 ASJ exome

AF:

0.0230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00789

Gnomad4 FIN exome

AF:

0.00697

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.00980

GnomAD4 genome

AF:

0.00748

AC:

1140

AN:

152324

Hom.:

Cov.:

AF XY:

0.00737

AC XY:

549

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00229

Gnomad4 AMR

AF:

0.00470

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00746

Gnomad4 FIN

AF:

0.00650

Gnomad4 NFE

AF:

0.0113

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00934

Hom.:

Bravo

AF:

0.00708

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dilated Cardiomyopathy, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

Cadd

Benign

0.0080

Dann

Benign

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over