Variant 1-15684588-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7

The NM_015164.4(PLEKHM2):c.30C>T(p.Ile10=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,313,212 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 0.000087 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000060 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.505

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 Benign. Variant got -9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 1-15684588-C-T is Benign according to our data. Variant chr1-15684588-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1540450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.505 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PLEKHM2	NM_015164.4 linkuse as main transcript	c.30C>T	p.Ile10=	synonymous_variant	1/20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1 linkuse as main transcript	c.30C>T	p.Ile10=	synonymous_variant	1/19		NP_001397684.1
PLEKHM2	XM_017000757.1 linkuse as main transcript	c.99+2889C>T		intron_variant			XP_016856246.1
PLEKHM2	XM_017000758.1 linkuse as main transcript	c.99+2889C>T		intron_variant			XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8 linkuse as main transcript	c.30C>T	p.Ile10=	synonymous_variant	1/20	1	NM_015164.4	ENSP00000364956	P2	Q8IWE5-1
PLEKHM2	ENST00000375793.2 linkuse as main transcript	c.30C>T	p.Ile10=	synonymous_variant	1/19	5		ENSP00000364950	A2	Q8IWE5-2
PLEKHM2	ENST00000642363.1 linkuse as main transcript	c.30C>T	p.Ile10=	synonymous_variant	1/21			ENSP00000494591	A2
PLEKHM2	ENST00000462455.1 linkuse as main transcript	n.48C>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000867

AC:

AN:

149968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000199

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:

0.00000602

AC:

AN:

1163244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

568154

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

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:

0.00000105

Gnomad4 OTH exome

AF:

0.0000226

GnomAD4 genome

AF:

0.0000867

AC:

AN:

149968

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

73190

show subpopulations

Gnomad4 AFR

AF:

0.000243

Gnomad4 AMR

AF:

0.000199

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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000125

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated Cardiomyopathy, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 27, 2022

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

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