rs143372200

Variant names:

• chr1-15727132-C-T
• rs143372200
• NM_015164.4:c.1060C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-15727132-C-T
• chr1-15727132-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_015164.4(PLEKHM2):​c.1060C>T​(p.Arg354Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,590,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. R354H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.21
• Publications: 1 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: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics

ENSG00000237938 (HGNC:58402):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032825768).
• BP6: Variant 1-15727132-C-T is Benign according to our data. Variant chr1-15727132-C-T is described in ClinVar as Benign. ClinVar VariationId is 478062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	NM_015164.4	MANE Select	c.1060C>T	p.Arg354Cys	missense	Exon 9 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.1000C>T	p.Arg334Cys	missense	Exon 8 of 19	NP_001397684.1	Q8IWE5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.1060C>T	p.Arg354Cys	missense	Exon 9 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.1168C>T	p.Arg390Cys	missense	Exon 10 of 21	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.1060C>T	p.Arg354Cys	missense	Exon 9 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000478 AC: 106 AN: 221866 AF XY: 0.000330

Gnomad AFR exome AF: 0.00718

Gnomad AMR exome AF: 0.000191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.000553

GnomAD4 exome AF: 0.000206 AC: 296 AN: 1438656 Hom.: 0 Cov.: 33 AF XY: 0.000177 AC XY: 126 AN XY: 712734

African (AFR) AF: 0.00609 AC: 201 AN: 33020

American (AMR) AF: 0.000380 AC: 16 AN: 42136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25186

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39020

South Asian (SAS) AF: 0.0000602 AC: 5 AN: 83050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51194

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5646

European-Non Finnish (NFE) AF: 0.0000391 AC: 43 AN: 1100018

Other (OTH) AF: 0.000488 AC: 29 AN: 59386

GnomAD4 genome AF: 0.00187 AC: 284 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74436

African (AFR) AF: 0.00628 AC: 261 AN: 41552

American (AMR) AF: 0.00118 AC: 18 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.00218

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00632 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000589 AC: 71

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated Cardiomyopathy, Recessive (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.71
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.061
Sift	Benign	0.20	T
Sift4G	Uncertain	0.054	T
Polyphen		0.0	B
Vest4		0.060
MVP		0.14
MPC		0.21
ClinPred		0.0061	T
GERP RS		0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.044
gMVP		0.10
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

Other links and lift over

dbSNP: rs143372200; hg19: chr1-16053627;