1-15716217-G-GGT

Variant names:

• chr1-15716217-G-GGT
• rs1571050078
• NM_015164.4:c.61-17_61-16dupGT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_015164.4(PLEKHM2):​c.61-17_61-16dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000652 in 1,227,398 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.128
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-15716217-G-GGT is Benign according to our data. Variant chr1-15716217-G-GGT is described in ClinVar as Likely_benign. ClinVar VariationId is 2911849.Status of the report is criteria_provided_single_submitter, 1 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.61-17_61-16dupGT		intron	N/A	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.61-17_61-16dupGT		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.61-20_61-19insGT		intron	N/A	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.61-20_61-19insGT		intron	N/A	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.61-20_61-19insGT		intron	N/A	ENSP00000627412.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000618 AC: 1 AN: 161858 AF XY: 0.0000116

Gnomad AFR exome AF: 0.00

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: 0.0000145

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000652 AC: 8 AN: 1227398 Hom.: 0 Cov.: 17 AF XY: 0.00000650 AC XY: 4 AN XY: 615228

African (AFR) AF: 0.00 AC: 0 AN: 26456

American (AMR) AF: 0.00 AC: 0 AN: 35152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23970

East Asian (EAS) AF: 0.00 AC: 0 AN: 36944

South Asian (SAS) AF: 0.00 AC: 0 AN: 74806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5270

European-Non Finnish (NFE) AF: 0.00000863 AC: 8 AN: 927526

Other (OTH) AF: 0.00 AC: 0 AN: 52536

GnomAD4 genome Cov.: 33

Alfa AF: 0.000112 Hom.: 0

ClinVar

ClinVar submissions

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
PhyloP100		-0.13

Splicing

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

Other links and lift over

dbSNP: rs1571050078; hg19: chr1-16042712;