1-15684510-GGGCGGC-GGGCGGCGGCGGCGGCGGGGCGGCGGC

Variant names:

• chr1-15684510-G-GGGCGGCGGCGGCGGCGGGGC
• rs767880122
• NM_015164.4:c.-35_-34insCGGGGCGGCGGCGGCGGCGG

Variant summary

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

The NM_015164.4(PLEKHM2):​c.-35_-34insCGGGGCGGCGGCGGCGGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.000014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLEKHM2 NM_015164.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0330
• Publications: 2 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.-35_-34insCGGGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.-35_-34insCGGGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 19	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.-35_-34insCGGGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957353.1		c.-35_-34insCGGGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 20	ENSP00000627412.1
	PLEKHM2	ENST00000957355.1		c.-35_-34insCGGGGCGGCGGCGGCGGCGG		5_prime_UTR	Exon 1 of 20	ENSP00000627414.1

Frequencies

GnomAD3 genomes AF: 0.0000139 AC: 2 AN: 144046 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000308

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000360 AC: 3 AN: 832706 Hom.: 0 Cov.: 17 AF XY: 0.00000256 AC XY: 1 AN XY: 390530

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

African (AFR) AF: 0.00 AC: 0 AN: 15288

American (AMR) AF: 0.00 AC: 0 AN: 2566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6460

East Asian (EAS) AF: 0.00 AC: 0 AN: 8036

South Asian (SAS) AF: 0.0000589 AC: 1 AN: 16992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2002

European-Non Finnish (NFE) AF: 0.00000272 AC: 2 AN: 734776

Other (OTH) AF: 0.00 AC: 0 AN: 28284

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000416442), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000139 AC: 2 AN: 144102 Hom.: 0 Cov.: 0 AF XY: 0.0000143 AC XY: 1 AN XY: 70004

African (AFR) AF: 0.00 AC: 0 AN: 40218

American (AMR) AF: 0.00 AC: 0 AN: 14666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3370

East Asian (EAS) AF: 0.00 AC: 0 AN: 4780

South Asian (SAS) AF: 0.00 AC: 0 AN: 4746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000308 AC: 2 AN: 64978

Other (OTH) AF: 0.00 AC: 0 AN: 2010

Alfa AF: 0.00 Hom.: 1087

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.033

Splicing

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

Other links and lift over

dbSNP: rs767880122; hg19: chr1-16011005;