rs201860640

Positions:

• chr1-15718592-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_015164.4(PLEKHM2):​c.432C>T​(p.Ser144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,394,892 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: PLEKHM2 NM_015164.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-15718592-C-T is Benign according to our data. Variant chr1-15718592-C-T is described in ClinVar as [Benign]. Clinvar id is 478099.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.69 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.432C>T	p.Ser144=	synonymous_variant	5/20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1	c.432C>T	p.Ser144=	synonymous_variant	5/19		NP_001397684.1
PLEKHM2	XM_017000757.1	c.471C>T	p.Ser157=	synonymous_variant	5/20		XP_016856246.1
PLEKHM2	XM_017000758.1	c.471C>T	p.Ser157=	synonymous_variant	5/19		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.432C>T	p.Ser144=	synonymous_variant	5/20	1	NM_015164.4	ENSP00000364956	P2
PLEKHM2	ENST00000375793.2	c.432C>T	p.Ser144=	synonymous_variant	5/19	5		ENSP00000364950	A2
PLEKHM2	ENST00000642363.1	c.432C>T	p.Ser144=	synonymous_variant	5/21			ENSP00000494591	A2
PLEKHM2	ENST00000462455.1	n.340C>T		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 206 AN: 141678 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.000243

Gnomad SAS AF: 0.000997

Gnomad FIN AF: 0.000111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00233

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00142 AC: 277 AN: 195340 Hom.: 0 AF XY: 0.00149 AC XY: 156 AN XY: 104764

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.000828

Gnomad ASJ exome AF: 0.000550

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.00262 AC: 3277 AN: 1253084 Hom.: 9 Cov.: 31 AF XY: 0.00264 AC XY: 1632 AN XY: 618346

Gnomad4 AFR exome AF: 0.000291

Gnomad4 AMR exome AF: 0.000836

Gnomad4 ASJ exome AF: 0.000528

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.000108

Gnomad4 NFE exome AF: 0.00307

Gnomad4 OTH exome AF: 0.00208

GnomAD4 genome AF: 0.00145 AC: 205 AN: 141808 Hom.: 0 Cov.: 31 AF XY: 0.00128 AC XY: 88 AN XY: 68626

Gnomad4 AFR AF: 0.000718

Gnomad4 AMR AF: 0.00130

Gnomad4 ASJ AF: 0.000298

Gnomad4 EAS AF: 0.000244

Gnomad4 SAS AF: 0.000994

Gnomad4 FIN AF: 0.000111

Gnomad4 NFE AF: 0.00233

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00186 Hom.: 1

Bravo AF: 0.00139

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

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.85

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: rs201860640; hg19: chr1-16045087;