rs116455686

Positions:

• chr1-15730534-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000375799.8(PLEKHM2):​c.2211A>G​(p.Ala737=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00993 in 1,577,064 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (7 hom., cov: 33)
  • Exomes 𝑓: 0.010 (101 hom.)
• Consequence: PLEKHM2 ENST00000375799.8 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.98

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-15730534-A-G is Benign according to our data. Variant chr1-15730534-A-G is described in ClinVar as [Benign]. Clinvar id is 478078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.98 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.2211A>G	p.Ala737=	splice_region_variant, synonymous_variant	15/20	ENST00000375799.8	NP_055979.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.2211A>G	p.Ala737=	splice_region_variant, synonymous_variant	15/20	1	NM_015164.4	ENSP00000364956	P2
	ENST00000453804.1	n.211+1853T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00750 AC: 1141 AN: 152208 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00808 AC: 1616 AN: 200000 Hom.: 11 AF XY: 0.00852 AC XY: 923 AN XY: 108386

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00332

Gnomad ASJ exome AF: 0.0205

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00743

Gnomad FIN exome AF: 0.00757

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0102 AC: 14517 AN: 1424740 Hom.: 101 Cov.: 32 AF XY: 0.0101 AC XY: 7151 AN XY: 705102

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00364

Gnomad4 ASJ exome AF: 0.0230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00789

Gnomad4 FIN exome AF: 0.00697

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00980

GnomAD4 genome AF: 0.00748 AC: 1140 AN: 152324 Hom.: 7 Cov.: 33 AF XY: 0.00737 AC XY: 549 AN XY: 74490

Gnomad4 AFR AF: 0.00229

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00934 Hom.: 2

Bravo AF: 0.00708

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PLEKHM2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dilated Cardiomyopathy, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0080
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs116455686; hg19: chr1-16057029;