chr1-15717972-G-C

Position:

• chr1-15717972-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The ENST00000375799.8(PLEKHM2):​c.357G>C​(p.Leu119=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,593,172 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: PLEKHM2 ENST00000375799.8 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.69

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-15717972-G-C is Benign according to our data. Variant chr1-15717972-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 478098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.69 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.357G>C	p.Leu119=	synonymous_variant	4/20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1	c.357G>C	p.Leu119=	synonymous_variant	4/19		NP_001397684.1
PLEKHM2	XM_017000757.1	c.396G>C	p.Leu132=	synonymous_variant	4/20		XP_016856246.1
PLEKHM2	XM_017000758.1	c.396G>C	p.Leu132=	synonymous_variant	4/19		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.357G>C	p.Leu119=	synonymous_variant	4/20	1	NM_015164.4	ENSP00000364956	P2
PLEKHM2	ENST00000375793.2	c.357G>C	p.Leu119=	synonymous_variant	4/19	5		ENSP00000364950	A2
PLEKHM2	ENST00000642363.1	c.357G>C	p.Leu119=	synonymous_variant	4/21			ENSP00000494591	A2
PLEKHM2	ENST00000462455.1	n.265G>C		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.000847 AC: 129 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000796 AC: 171 AN: 214950 Hom.: 0 AF XY: 0.000871 AC XY: 101 AN XY: 115948

Gnomad AFR exome AF: 0.000322

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000225

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.000552

GnomAD4 exome AF: 0.00152 AC: 2191 AN: 1440816 Hom.: 3 Cov.: 30 AF XY: 0.00147 AC XY: 1051 AN XY: 714918

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.000597

Gnomad4 ASJ exome AF: 0.0000780

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000326

Gnomad4 FIN exome AF: 0.000134

Gnomad4 NFE exome AF: 0.00185

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74512

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00118 Hom.: 1

Bravo AF: 0.000903

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.7
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201114976; hg19: chr1-16044467;