rs200036096

Variant names:

• chr1-15727749-C-T
• rs200036096
• NM_015164.4:c.1677C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_015164.4(PLEKHM2):​c.1677C>T​(p.Ser559Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,603,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: PLEKHM2 NM_015164.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.249
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-15727749-C-T is Benign according to our data. Variant chr1-15727749-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 478071.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.249 with no splicing effect.

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.1677C>T	p.Ser559Ser	synonymous	Exon 9 of 20	NP_055979.2
	PLEKHM2	NM_001410755.1		c.1617C>T	p.Ser539Ser	synonymous	Exon 8 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.1677C>T	p.Ser559Ser	synonymous	Exon 9 of 20	ENSP00000364956.3
	PLEKHM2	ENST00000850891.1		c.1716C>T	p.Ser572Ser	synonymous	Exon 9 of 20	ENSP00000520968.1
	PLEKHM2	ENST00000375793.3	TSL:5	c.1617C>T	p.Ser539Ser	synonymous	Exon 8 of 19	ENSP00000364950.2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000632

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000275 AC: 63 AN: 228768 AF XY: 0.000305

Gnomad AFR exome AF: 0.000148

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: 0.000588

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000697 AC: 1011 AN: 1451424 Hom.: 1 Cov.: 33 AF XY: 0.000664 AC XY: 479 AN XY: 720916

African (AFR) AF: 0.000180 AC: 6 AN: 33310

American (AMR) AF: 0.0000231 AC: 1 AN: 43222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 84200

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000877 AC: 972 AN: 1107974

Other (OTH) AF: 0.000516 AC: 31 AN: 60028

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74416

African (AFR) AF: 0.000169 AC: 7 AN: 41522

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000348

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated Cardiomyopathy, Recessive (1)
-	-	1	PLEKHM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.0
DANN	Benign	0.72
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200036096; hg19: chr1-16054244;