chr1-15684510-GGGC-G

Variant names:

• chr1-15684510-GGGC-G
• rs767880122
• NM_015164.4:c.-37_-35delCGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_015164.4(PLEKHM2):​c.-37_-35delCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 976,542 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0031 (4 hom.)
• Consequence: PLEKHM2 NM_015164.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200
• 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: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.-37_-35delCGG		5_prime_UTR	Exon 1 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.-37_-35delCGG		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.-37_-35delCGG		5_prime_UTR	Exon 1 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957353.1		c.-37_-35delCGG		5_prime_UTR	Exon 1 of 20	ENSP00000627412.1
	PLEKHM2	ENST00000957355.1		c.-37_-35delCGG		5_prime_UTR	Exon 1 of 20	ENSP00000627414.1

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 367 AN: 144044 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00266

Gnomad ASJ AF: 0.00326

Gnomad EAS AF: 0.000208

Gnomad SAS AF: 0.00568

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0130

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00301

GnomAD2 exomes AF: 0.000910 AC: 9 AN: 9892 AF XY: 0.00125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0556

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000240

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00308 AC: 2568 AN: 832442 Hom.: 4 AF XY: 0.00315 AC XY: 1230 AN XY: 390400

African (AFR) AF: 0.00196 AC: 30 AN: 15288

American (AMR) AF: 0.00273 AC: 7 AN: 2564

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 41 AN: 6458

East Asian (EAS) AF: 0.000125 AC: 1 AN: 8030

South Asian (SAS) AF: 0.00712 AC: 121 AN: 16988

European-Finnish (FIN) AF: 0.000437 AC: 8 AN: 18302

Middle Eastern (MID) AF: 0.0130 AC: 26 AN: 2002

European-Non Finnish (NFE) AF: 0.00305 AC: 2239 AN: 734534

Other (OTH) AF: 0.00336 AC: 95 AN: 28276

GnomAD4 genome AF: 0.00257 AC: 370 AN: 144100 Hom.: 1 Cov.: 0 AF XY: 0.00233 AC XY: 163 AN XY: 70002

African (AFR) AF: 0.00179 AC: 72 AN: 40218

American (AMR) AF: 0.00266 AC: 39 AN: 14666

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 11 AN: 3370

East Asian (EAS) AF: 0.000209 AC: 1 AN: 4780

South Asian (SAS) AF: 0.00590 AC: 28 AN: 4746

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

Middle Eastern (MID) AF: 0.0141 AC: 4 AN: 284

European-Non Finnish (NFE) AF: 0.00322 AC: 209 AN: 64978

Other (OTH) AF: 0.00299 AC: 6 AN: 2008

Alfa AF: 0.000369 Hom.: 1087

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0020
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs767880122; hg19: chr1-16011005;