rs536599433

Variant names:

• chr1-15732471-C-T
• rs536599433
• NM_015164.4:c.2747C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015164.4(PLEKHM2):​c.2747C>T​(p.Ala916Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,604,830 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.29

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]

ENSG00000237938 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005495578).
• BP6: Variant 1-15732471-C-T is Benign according to our data. Variant chr1-15732471-C-T is described in ClinVar as [Benign]. Clinvar id is 478092.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.2747C>T	p.Ala916Val	missense_variant	Exon 18 of 20	ENST00000375799.8	NP_055979.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.2747C>T	p.Ala916Val	missense_variant	Exon 18 of 20	1	NM_015164.4	ENSP00000364956.3

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152196 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000849 AC: 198 AN: 233114 AF XY: 0.00116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000953

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000412 AC: 599 AN: 1452516 Hom.: 3 Cov.: 32 AF XY: 0.000615 AC XY: 444 AN XY: 721680

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33370

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 43324

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25860

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39418

Gnomad4 SAS exome AF: 0.00676 AC: 572 AN: 84604

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52106

Gnomad4 NFE exome AF: 9.02e-7 AC: 1 AN: 1108060

Gnomad4 Remaining exome AF: 0.000400 AC: 24 AN: 60018

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152314 Hom.: 3 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74478

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00890 AC: 0.00890269 AN: 0.00890269

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000812 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000928 AC: 112

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Benign:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.077
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.72	N;N;.
REVEL	Benign	0.077
Sift	Benign	0.37	T;T;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0010	B;.;.
Vest4		0.31
MutPred		0.24		Gain of sheet (P = 0.0149);.;.;
MVP		0.30
MPC		0.15
ClinPred		0.047	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.59
Mutation Taster		=98/2	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

Publications

LitVar

Other links and lift over

dbSNP: rs536599433; hg19: chr1-16058966;