NM_015164.4:c.61-7delC

Variant names:

• chr1-15716229-TC-T
• rs66610224
• NM_015164.4:c.61-7delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_015164.4(PLEKHM2):​c.61-7delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,448,598 control chromosomes in the GnomAD database, including 7,584 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2833 hom., cov: 32)
  • Exomes 𝑓: 0.14 (4751 hom.)
• Consequence: PLEKHM2 NM_015164.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.281
• Publications: 4 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-15716229-TC-T is Benign according to our data. Variant chr1-15716229-TC-T is described in ClinVar as Benign. ClinVar VariationId is 1165087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.233 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.61-7delC		splice_region intron	N/A	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.61-7delC		splice_region 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.61-7delC		splice_region intron	N/A	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.61-7delC		splice_region intron	N/A	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.61-7delC		splice_region intron	N/A	ENSP00000627412.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28657 AN: 150756 Hom.: 2831 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.201

GnomAD2 exomes AF: 0.117 AC: 20353 AN: 174396 AF XY: 0.117

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.0781

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.0192

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.140 AC: 181779 AN: 1297730 Hom.: 4751 Cov.: 18 AF XY: 0.141 AC XY: 90783 AN XY: 645624

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

African (AFR) AF: 0.186 AC: 5207 AN: 27950

American (AMR) AF: 0.0836 AC: 3012 AN: 36038

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 3926 AN: 23854

East Asian (EAS) AF: 0.0457 AC: 1736 AN: 37950

South Asian (SAS) AF: 0.111 AC: 8419 AN: 75676

European-Finnish (FIN) AF: 0.149 AC: 6698 AN: 45040

Middle Eastern (MID) AF: 0.207 AC: 1091 AN: 5270

European-Non Finnish (NFE) AF: 0.145 AC: 144033 AN: 991310

Other (OTH) AF: 0.140 AC: 7657 AN: 54642

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.190 AC: 28679 AN: 150868 Hom.: 2833 Cov.: 32 AF XY: 0.186 AC XY: 13725 AN XY: 73656

African (AFR) AF: 0.237 AC: 9735 AN: 41010

American (AMR) AF: 0.137 AC: 2076 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 692 AN: 3458

East Asian (EAS) AF: 0.0303 AC: 157 AN: 5180

South Asian (SAS) AF: 0.115 AC: 551 AN: 4786

European-Finnish (FIN) AF: 0.163 AC: 1673 AN: 10238

Middle Eastern (MID) AF: 0.240 AC: 69 AN: 288

European-Non Finnish (NFE) AF: 0.193 AC: 13076 AN: 67740

Other (OTH) AF: 0.203 AC: 425 AN: 2090

Alfa AF: 0.0376 Hom.: 66

Asia WGS AF: 0.105 AC: 363 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated Cardiomyopathy, Recessive (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.28
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs66610224; hg19: chr1-16042724;