chr1-15719829-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_015164.4(PLEKHM2):c.561C>T(p.His187His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00548 in 1,613,820 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0056 ( 48 hom. )

Consequence

PLEKHM2
NM_015164.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.91

Publications

1 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: LIMITED Submitted by: ClinGen, Ambry Genetics

PLEKHM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 1-15719829-C-T is Benign according to our data. Variant chr1-15719829-C-T is described in ClinVar as Benign. ClinVar VariationId is 478101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.91 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0056 (8186/1461530) while in subpopulation MID AF = 0.0232 (134/5768). AF 95% confidence interval is 0.02. There are 48 homozygotes in GnomAdExome4. There are 4024 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PLEKHM2	NM_015164.4 link	c.561C>T	p.His187His	synonymous_variant	Exon 6 of 20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1 link	c.561C>T	p.His187His	synonymous_variant	Exon 6 of 19		NP_001397684.1
PLEKHM2	XM_017000757.1 link	c.600C>T	p.His200His	synonymous_variant	Exon 6 of 20		XP_016856246.1
PLEKHM2	XM_017000758.1 link	c.600C>T	p.His200His	synonymous_variant	Exon 6 of 19		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8 link	c.561C>T	p.His187His	synonymous_variant	Exon 6 of 20	1	NM_015164.4	ENSP00000364956.3		Q8IWE5-1

Frequencies

GnomAD3 genomes

AF:

0.00430

AC:

654

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00623

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00455

AC:

1134

AN:

249198

AF XY:

0.00448

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00267

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.000464

Gnomad NFE exome

AF:

0.00694

Gnomad OTH exome

AF:

0.00777

GnomAD4 exome

AF:

0.00560

AC:

8186

AN:

1461530

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

4024

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33472

American (AMR)

AF:

0.00304

AC:

136

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

422

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.00109

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.000805

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.0232

AC:

134

AN:

5768

European-Non Finnish (NFE)

AF:

0.00630

AC:

7001

AN:

1111738

Other (OTH)

AF:

0.00510

AC:

308

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

414

828

1243

1657

2071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

240

480

720

960

1200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00429

AC:

654

AN:

152290

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

308

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41550

American (AMR)

AF:

0.00497

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00622

AC:

423

AN:

68028

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00703

Hom.:

Bravo

AF:

0.00475

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00774

EpiControl

AF:

0.00634

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated Cardiomyopathy, Recessive

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

2.1

(source)

DANN

Benign

0.90

PhyloP100

-3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over