1-15684697-G-GGCGACCCTGCTGCCGCAGGGACTC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_015164.4(PLEKHM2):​c.60+80_60+81insCGACCCTGCTGCCGCAGGGACTCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 794,356 control chromosomes in the GnomAD database, including 38,002 homozygotes. 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (13259 hom., cov: 0)
  • Exomes 𝑓: 0.25 (24743 hom.)
• Consequence: PLEKHM2 NM_015164.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-15684697-G-GGCGACCCTGCTGCCGCAGGGACTC is Benign according to our data. Variant chr1-15684697-G-GGCGACCCTGCTGCCGCAGGGACTC is described in ClinVar as Benign. ClinVar VariationId is 1231190.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55054 AN: 150178 Hom.: 13216 Cov.: 0

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.0309

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.351

GnomAD4 exome AF: 0.250 AC: 160789 AN: 644070 Hom.: 24743 AF XY: 0.249 AC XY: 76740 AN XY: 307976

African (AFR) AF: 0.710 AC: 9288 AN: 13086

American (AMR) AF: 0.197 AC: 878 AN: 4452

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 2178 AN: 7518

East Asian (EAS) AF: 0.0594 AC: 929 AN: 15638

South Asian (SAS) AF: 0.217 AC: 2593 AN: 11960

European-Finnish (FIN) AF: 0.287 AC: 8133 AN: 28338

Middle Eastern (MID) AF: 0.315 AC: 623 AN: 1976

European-Non Finnish (NFE) AF: 0.242 AC: 129973 AN: 536634

Other (OTH) AF: 0.253 AC: 6194 AN: 24468

GnomAD4 genome AF: 0.367 AC: 55152 AN: 150286 Hom.: 13259 Cov.: 0 AF XY: 0.362 AC XY: 26571 AN XY: 73368

African (AFR) AF: 0.679 AC: 27861 AN: 41024

American (AMR) AF: 0.225 AC: 3423 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 998 AN: 3458

East Asian (EAS) AF: 0.0308 AC: 155 AN: 5040

South Asian (SAS) AF: 0.197 AC: 944 AN: 4780

European-Finnish (FIN) AF: 0.296 AC: 3032 AN: 10234

Middle Eastern (MID) AF: 0.300 AC: 87 AN: 290

European-Non Finnish (NFE) AF: 0.262 AC: 17626 AN: 67278

Other (OTH) AF: 0.352 AC: 736 AN: 2090

Alfa AF: 0.0943 Hom.: 171

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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;