1-15725495-G-C

Variant names:

• chr1-15725495-G-C
• rs61738982
• NM_015164.4:c.891G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015164.4(PLEKHM2):​c.891G>C​(p.Glu297Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,580,838 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E297A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (29 hom.)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.269
• Publications: 3 publications found

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

ENSG00000237938 (HGNC:58402):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027320385).
• BP6: Variant 1-15725495-G-C is Benign according to our data. Variant chr1-15725495-G-C is described in ClinVar as Benign. ClinVar VariationId is 478105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 29 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015164.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	NM_015164.4	MANE Select	c.891G>C	p.Glu297Asp	missense	Exon 8 of 20	NP_055979.2
	PLEKHM2	NM_001410755.1		c.831G>C	p.Glu277Asp	missense	Exon 7 of 19	NP_001397684.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.891G>C	p.Glu297Asp	missense	Exon 8 of 20	ENSP00000364956.3
	PLEKHM2	ENST00000850891.1		c.930G>C	p.Glu310Asp	missense	Exon 8 of 20	ENSP00000520968.1
	PLEKHM2	ENST00000375793.3	TSL:5	c.831G>C	p.Glu277Asp	missense	Exon 7 of 19	ENSP00000364950.2

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00413 AC: 812 AN: 196436 AF XY: 0.00417

Gnomad AFR exome AF: 0.000662

Gnomad AMR exome AF: 0.00354

Gnomad ASJ exome AF: 0.00763

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00384

Gnomad NFE exome AF: 0.00583

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.00432 AC: 6171 AN: 1428472 Hom.: 29 Cov.: 31 AF XY: 0.00439 AC XY: 3105 AN XY: 707396

African (AFR) AF: 0.000678 AC: 22 AN: 32426

American (AMR) AF: 0.00379 AC: 153 AN: 40338

Ashkenazi Jewish (ASJ) AF: 0.00943 AC: 241 AN: 25554

East Asian (EAS) AF: 0.00 AC: 0 AN: 37404

South Asian (SAS) AF: 0.00160 AC: 130 AN: 81148

European-Finnish (FIN) AF: 0.00341 AC: 172 AN: 50372

Middle Eastern (MID) AF: 0.00316 AC: 18 AN: 5702

European-Non Finnish (NFE) AF: 0.00472 AC: 5173 AN: 1096308

Other (OTH) AF: 0.00442 AC: 262 AN: 59220

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152366 Hom.: 0 Cov.: 32 AF XY: 0.00315 AC XY: 235 AN XY: 74508

African (AFR) AF: 0.000793 AC: 33 AN: 41588

American (AMR) AF: 0.00268 AC: 41 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00523 AC: 356 AN: 68040

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00475 Hom.: 2

Bravo AF: 0.00313

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000504 AC: 2

ESP6500EA AF: 0.00592 AC: 49

ExAC AF: 0.00328 AC: 392

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Benign:1

Jan 20, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.27
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.029
Sift	Benign	0.17	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.098
MutPred		0.092		Loss of glycosylation at K295 (P = 0.1881)
MVP		0.19
MPC		0.14
ClinPred		0.0011	T
GERP RS		-0.21
Varity_R		0.055
gMVP		0.045
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs61738982; hg19: chr1-16051990;