NM_015164.4:c.-37_-35dupCGG

Variant names:

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

Variant summary

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

The NM_015164.4(PLEKHM2):​c.-37_-35dupCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.66 (31946 hom., cov: 0)
  • Exomes 𝑓: 0.60 (145345 hom.)
• Consequence: PLEKHM2 NM_015164.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-15684510-G-GGGC is Benign according to our data. Variant chr1-15684510-G-GGGC is described in ClinVar as Benign. ClinVar VariationId is 1276290.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 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.-37_-35dupCGG		5_prime_UTR	Exon 1 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.-37_-35dupCGG		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_-35dupCGG		5_prime_UTR	Exon 1 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957353.1		c.-37_-35dupCGG		5_prime_UTR	Exon 1 of 20	ENSP00000627412.1
	PLEKHM2	ENST00000957355.1		c.-37_-35dupCGG		5_prime_UTR	Exon 1 of 20	ENSP00000627414.1

Frequencies

GnomAD3 genomes AF: 0.659 AC: 94867 AN: 143930 Hom.: 31917 Cov.: 0

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.765

Gnomad MID AF: 0.555

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.619

GnomAD2 exomes AF: 0.693 AC: 6854 AN: 9892 AF XY: 0.676

Gnomad AFR exome AF: 0.421

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.438

Gnomad FIN exome AF: 0.735

Gnomad NFE exome AF: 0.516

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.597 AC: 495183 AN: 829998 Hom.: 145345 Cov.: 17 AF XY: 0.596 AC XY: 231920 AN XY: 389264

African (AFR) AF: 0.735 AC: 11200 AN: 15244

American (AMR) AF: 0.453 AC: 1155 AN: 2552

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 3563 AN: 6442

East Asian (EAS) AF: 0.570 AC: 4555 AN: 7990

South Asian (SAS) AF: 0.469 AC: 7938 AN: 16924

European-Finnish (FIN) AF: 0.727 AC: 13220 AN: 18188

Middle Eastern (MID) AF: 0.496 AC: 988 AN: 1990

European-Non Finnish (NFE) AF: 0.596 AC: 436245 AN: 732498

Other (OTH) AF: 0.579 AC: 16319 AN: 28170

GnomAD4 genome AF: 0.659 AC: 94923 AN: 143986 Hom.: 31946 Cov.: 0 AF XY: 0.660 AC XY: 46138 AN XY: 69948

African (AFR) AF: 0.758 AC: 30457 AN: 40196

American (AMR) AF: 0.544 AC: 7978 AN: 14656

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2028 AN: 3368

East Asian (EAS) AF: 0.619 AC: 2956 AN: 4776

South Asian (SAS) AF: 0.479 AC: 2275 AN: 4746

European-Finnish (FIN) AF: 0.765 AC: 6246 AN: 8160

Middle Eastern (MID) AF: 0.567 AC: 161 AN: 284

European-Non Finnish (NFE) AF: 0.631 AC: 40973 AN: 64918

Other (OTH) AF: 0.621 AC: 1247 AN: 2008

Alfa AF: 0.371 Hom.: 1087

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		-0.033
Mutation Taster		=300/0	polymorphism (auto)

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; COSMIC: COSV65395650; COSMIC: COSV65395650;