rs542980745

Variant names:

• chr1-15725528-G-A
• rs542980745
• NM_015164.4:c.924G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-15725528-G-A
• chr1-15725528-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_015164.4(PLEKHM2):​c.924G>A​(p.Thr308Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,566,564 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: PLEKHM2 NM_015164.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.65
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-15725528-G-A is Benign according to our data. Variant chr1-15725528-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 478106.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.65 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.924G>A	p.Thr308Thr	synonymous	Exon 8 of 20	NP_055979.2
	PLEKHM2	NM_001410755.1		c.864G>A	p.Thr288Thr	synonymous	Exon 7 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.924G>A	p.Thr308Thr	synonymous	Exon 8 of 20	ENSP00000364956.3
	PLEKHM2	ENST00000957356.1		c.1032G>A	p.Thr344Thr	synonymous	Exon 9 of 21	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.924G>A	p.Thr308Thr	synonymous	Exon 8 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000369 AC: 64 AN: 173402 AF XY: 0.000431

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000280

Gnomad OTH exome AF: 0.000212

GnomAD4 exome AF: 0.000170 AC: 240 AN: 1414212 Hom.: 2 Cov.: 31 AF XY: 0.000230 AC XY: 161 AN XY: 699110

African (AFR) AF: 0.0000623 AC: 2 AN: 32078

American (AMR) AF: 0.000184 AC: 7 AN: 38010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25380

East Asian (EAS) AF: 0.0000819 AC: 3 AN: 36638

South Asian (SAS) AF: 0.00235 AC: 188 AN: 80070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49298

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5492

European-Non Finnish (NFE) AF: 0.0000276 AC: 30 AN: 1088558

Other (OTH) AF: 0.000153 AC: 9 AN: 58688

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74502

African (AFR) AF: 0.000120 AC: 5 AN: 41596

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000447 Hom.: 0

Bravo AF: 0.0000718

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.21
DANN	Benign	0.75
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs542980745; hg19: chr1-16052023; COSMIC: COSV105312168; COSMIC: COSV105312168;