rs61738983

Positions:

• chr1-15727156-C-G
• chr1-15727156-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015164.4(PLEKHM2):​c.1084C>G​(p.Arg362Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,597,150 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. R362L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (15 hom.)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.57

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029738247).
• BP6: Variant 1-15727156-C-G is Benign according to our data. Variant chr1-15727156-C-G is described in ClinVar as [Benign]. Clinvar id is 478063.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00711 (1083/152230) while in subpopulation AFR AF= 0.0245 (1018/41532). AF 95% confidence interval is 0.0233. There are 13 homozygotes in gnomad4. There are 503 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM2	NM_015164.4	c.1084C>G	p.Arg362Gly	missense_variant	9/20	ENST00000375799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.1084C>G	p.Arg362Gly	missense_variant	9/20	1	NM_015164.4	P2
	ENST00000453804.1	n.212-3869G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00712 AC: 1083 AN: 152112 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00162 AC: 370 AN: 228468 Hom.: 5 AF XY: 0.00111 AC XY: 139 AN XY: 125130

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000353

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000492

Gnomad OTH exome AF: 0.000717

GnomAD4 exome AF: 0.000714 AC: 1032 AN: 1444920 Hom.: 15 Cov.: 33 AF XY: 0.000618 AC XY: 443 AN XY: 716532

Gnomad4 AFR exome AF: 0.0244

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000594

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000344

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00711 AC: 1083 AN: 152230 Hom.: 13 Cov.: 32 AF XY: 0.00676 AC XY: 503 AN XY: 74432

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.000387 Hom.: 0

Bravo AF: 0.00832

ESP6500AA AF: 0.0149 AC: 61

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00176 AC: 212

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.10
Sift	Benign	0.033	D;D
Sift4G	Benign	0.39	T;T
Polyphen		0.0	B;.
Vest4		0.057
MVP		0.18
MPC		0.20
ClinPred		0.0026	T
GERP RS		2.0
Varity_R		0.079
gMVP		0.089

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs61738983; hg19: chr1-16053651;