Genetic Variant NM_015164.4:c.60+80_60+81insCGACCCTGCTGCAGGGACTCG (chr1-15684697-G-GGCGACCCTGCTGCAGGGACTC) – ACMG Classification: Uncertain_significance (0 pts)

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+81insCGACCCTGCTGCAGGGACTCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 644,948 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: not found (cov: 0)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

Publications

0 publications found

Variant links:

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

PLEKHM2 links:

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ACMG classification

Classification was made for transcript

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+81insCGACCCTGCTGCAGGGACTCG		intron	N/A	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.60+80_60+81insCGACCCTGCTGCAGGGACTCG		intron	N/A	NP_001397684.1	Q8IWE5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.60+79_60+80insGCGACCCTGCTGCAGGGACTC	intron	N/A	ENSP00000364956.3	Q8IWE5-1
PLEKHM2	ENST00000957356.1		c.60+79_60+80insGCGACCCTGCTGCAGGGACTC	intron	N/A	ENSP00000627415.1
PLEKHM2	ENST00000957353.1		c.60+79_60+80insGCGACCCTGCTGCAGGGACTC	intron	N/A	ENSP00000627412.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000155

AC:

AN:

644948

Hom.:

AF XY:

0.00000324

AC XY:

AN XY:

308400

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

13106

American (AMR)

AF:

0.00

AC:

AN:

4464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7530

East Asian (EAS)

AF:

0.00

AC:

AN:

15648

South Asian (SAS)

AF:

0.00

AC:

AN:

11966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1978

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

537354

Other (OTH)

AF:

0.00

AC:

AN:

24508

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over