1-15716220-G-GT

Position:

• chr1-15716220-G-GT

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_015164.4(PLEKHM2):​c.61-8dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,366,364 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-15716220-G-GT is Benign according to our data. Variant chr1-15716220-G-GT is described in ClinVar as [Benign]. Clinvar id is 1934598.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.61-8dup		splice_polypyrimidine_tract_variant, intron_variant		1	NM_015164.4	ENSP00000364956	P2
PLEKHM2	ENST00000375793.2	c.61-8dup		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000364950	A2
PLEKHM2	ENST00000642363.1	c.61-8dup		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000494591	A2
PLEKHM2	ENST00000462455.1	n.79-8dup		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000400 AC: 6 AN: 149868 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000594

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00288 AC: 3504 AN: 1216496 Hom.: 0 Cov.: 20 AF XY: 0.00276 AC XY: 1680 AN XY: 608478

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.00182

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.000811

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.00179

Gnomad4 NFE exome AF: 0.00327

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.0000400 AC: 6 AN: 149868 Hom.: 0 Cov.: 32 AF XY: 0.0000547 AC XY: 4 AN XY: 73126

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000664

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000594

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs3830503; hg19: chr1-16042715;