1-15725495-G-C

Position:

• chr1-15725495-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate 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. 13/20 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, single submitter B:1
• Conservation: PhyloP100: 0.269

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 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 id is 478105.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM2	NM_015164.4	c.891G>C	p.Glu297Asp	missense_variant	8/20	ENST00000375799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.891G>C	p.Glu297Asp	missense_variant	8/20	1	NM_015164.4	P2
	ENST00000453804.1	n.212-2208C>G		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.00413 AC: 812 AN: 196436 Hom.: 3 AF XY: 0.00417 AC XY: 442 AN XY: 105926

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 SAS exome AF: 0.00145

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

Gnomad4 AFR exome AF: 0.000678

Gnomad4 AMR exome AF: 0.00379

Gnomad4 ASJ exome AF: 0.00943

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00341

Gnomad4 NFE exome AF: 0.00472

Gnomad4 OTH exome AF: 0.00442

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

Gnomad4 AFR AF: 0.000793

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.00523

Gnomad4 OTH AF: 0.00474

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.13	N;N;.
REVEL	Benign	0.029
Sift	Benign	0.17	T;T;.
Sift4G	Benign	0.36	T;T;.
Polyphen		0.0010	B;.;.
Vest4		0.098
MutPred		0.092		Loss of glycosylation at K295 (P = 0.1881);.;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

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

Other links and lift over

dbSNP: rs61738982; hg19: chr1-16051990;