rs367663991

chr1-15716228-TTC-T

Variant summary

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

The NM_015164.4(PLEKHM2):c.61-7_61-6del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,421,724 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-15716228-TTC-T is Benign according to our data. Variant chr1-15716228-TTC-T is described in ClinVar as [Benign]. Clinvar id is 478102.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM2	NM_015164.4	c.61-7_61-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000375799.8
PLEKHM2	NM_001410755.1	c.61-7_61-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PLEKHM2	XM_017000757.1	c.100-7_100-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PLEKHM2	XM_017000758.1	c.100-7_100-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.61-7_61-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015164.4	P2
PLEKHM2	ENST00000375793.2	c.61-7_61-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A2
PLEKHM2	ENST00000642363.1	c.61-7_61-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				A2
PLEKHM2	ENST00000462455.1	n.79-7_79-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150632 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000287

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00256 AC: 3257 AN: 1270980 Hom.: 0 AF XY: 0.00250 AC XY: 1580 AN XY: 631406

Gnomad4 AFR exome AF: 0.00477

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00286

Gnomad4 EAS exome AF: 0.000294

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.00347

Gnomad4 NFE exome AF: 0.00267

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.0000398 AC: 6 AN: 150744 Hom.: 0 Cov.: 31 AF XY: 0.0000543 AC XY: 4 AN XY: 73690

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000287

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs367663991; hg19: chr1-16042723;