1-15716229-TC-T

Position:

• chr1-15716229-TC-T

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.61-7delC		splice_region_variant, intron_variant		ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1	c.61-7delC		splice_region_variant, intron_variant			NP_001397684.1
PLEKHM2	XM_017000757.1	c.100-7delC		splice_region_variant, intron_variant			XP_016856246.1
PLEKHM2	XM_017000758.1	c.100-7delC		splice_region_variant, intron_variant			XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.61-7delC		splice_region_variant, intron_variant		1	NM_015164.4	ENSP00000364956.3
PLEKHM2	ENST00000375793.2	c.61-7delC		splice_region_variant, intron_variant		5		ENSP00000364950.2
PLEKHM2	ENST00000642363.1	c.61-7delC		splice_region_variant, intron_variant				ENSP00000494591.1
PLEKHM2	ENST00000462455.1	n.79-7delC		splice_region_variant, intron_variant		5

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

GnomAD3 exomes AF: 0.117 AC: 20353 AN: 174396 Hom.: 202 AF XY: 0.117 AC XY: 10967 AN XY: 93506

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 SAS exome AF: 0.103

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

Gnomad4 AFR exome AF: 0.186

Gnomad4 AMR exome AF: 0.0836

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.0457

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.140

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

Gnomad4 AFR AF: 0.237

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.0303

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.203

Alfa AF: 0.0376 Hom.: 66

Asia WGS AF: 0.105 AC: 363 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs66610224; hg19: chr1-16042724;