1-15684697-G-GGCGACCCTGCTGCAGCAGGGACTC

Variant names:

• chr1-15684697-G-GGCGACCCTGCTGCAGCAGGGACTC
• rs369410677
• NM_015164.4:c.60+80_60+81insCGACCCTGCTGCAGCAGGGACTCG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_015164.4(PLEKHM2):​c.60+80_60+81insCGACCCTGCTGCAGCAGGGACTCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 795,264 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000093 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• 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: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.60+80_60+81insCGACCCTGCTGCAGCAGGGACTCG		intron	N/A	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.60+80_60+81insCGACCCTGCTGCAGCAGGGACTCG		intron	N/A	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.60+79_60+80insGCGACCCTGCTGCAGCAGGGACTC		intron	N/A	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.60+79_60+80insGCGACCCTGCTGCAGCAGGGACTC		intron	N/A	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.60+79_60+80insGCGACCCTGCTGCAGCAGGGACTC		intron	N/A	ENSP00000627412.1

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 31 AN: 150316 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000930 AC: 6 AN: 644948 Hom.: 0 AF XY: 0.0000130 AC XY: 4 AN XY: 308400

African (AFR) AF: 0.000153 AC: 2 AN: 13106

American (AMR) AF: 0.00 AC: 0 AN: 4464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7530

East Asian (EAS) AF: 0.00 AC: 0 AN: 15648

South Asian (SAS) AF: 0.00 AC: 0 AN: 11966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1978

European-Non Finnish (NFE) AF: 0.00000558 AC: 3 AN: 537354

Other (OTH) AF: 0.0000408 AC: 1 AN: 24508

GnomAD4 genome AF: 0.000206 AC: 31 AN: 150316 Hom.: 0 Cov.: 0 AF XY: 0.000150 AC XY: 11 AN XY: 73320

African (AFR) AF: 0.000733 AC: 30 AN: 40944

American (AMR) AF: 0.0000659 AC: 1 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67338

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 171

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs369410677; hg19: chr1-16011192;