1-15716230-C-T

Variant names:

• chr1-15716230-C-T
• rs76932674
• NM_015164.4:c.61-7C>T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015164.4(PLEKHM2):​c.61-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00641 in 1,244,082 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (12 hom.)
• Consequence: PLEKHM2 NM_015164.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004132
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-15716230-C-T is Benign according to our data. Variant chr1-15716230-C-T is described in ClinVar as [Benign]. Clinvar id is 478103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.61-7C>T		splice_region_variant, intron_variant	Intron 1 of 19	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1	c.61-7C>T		splice_region_variant, intron_variant	Intron 1 of 18		NP_001397684.1
PLEKHM2	XM_017000757.1	c.100-7C>T		splice_region_variant, intron_variant	Intron 1 of 19		XP_016856246.1
PLEKHM2	XM_017000758.1	c.100-7C>T		splice_region_variant, intron_variant	Intron 1 of 18		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.61-7C>T		splice_region_variant, intron_variant	Intron 1 of 19	1	NM_015164.4	ENSP00000364956.3
PLEKHM2	ENST00000375793.2	c.61-7C>T		splice_region_variant, intron_variant	Intron 1 of 18	5		ENSP00000364950.2
PLEKHM2	ENST00000642363.1	c.61-7C>T		splice_region_variant, intron_variant	Intron 1 of 20			ENSP00000494591.1
PLEKHM2	ENST00000462455.1	n.79-7C>T		splice_region_variant, intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 183 AN: 140168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000682

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000759

Gnomad ASJ AF: 0.00157

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00500

Gnomad FIN AF: 0.000537

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00177

Gnomad OTH AF: 0.00155

GnomAD4 exome AF: 0.00706 AC: 7793 AN: 1103828 Hom.: 12 Cov.: 18 AF XY: 0.00707 AC XY: 3841 AN XY: 542924

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.00462

Gnomad4 ASJ exome AF: 0.00758

Gnomad4 EAS exome AF: 0.000437

Gnomad4 SAS exome AF: 0.00951

Gnomad4 FIN exome AF: 0.00470

Gnomad4 NFE exome AF: 0.00724

Gnomad4 OTH exome AF: 0.00671

GnomAD4 genome AF: 0.00131 AC: 184 AN: 140254 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 94 AN XY: 68550

Gnomad4 AFR AF: 0.000707

Gnomad4 AMR AF: 0.000758

Gnomad4 ASJ AF: 0.00157

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00500

Gnomad4 FIN AF: 0.000537

Gnomad4 NFE AF: 0.00177

Gnomad4 OTH AF: 0.00154

Alfa AF: 0.107 Hom.: 263

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated Cardiomyopathy, Recessive Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

PLEKHM2-related disorder Benign:1

May 03, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.8
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.030		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: rs76932674; hg19: chr1-16042725;