1-15716230-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

PLEKHM2 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 478103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015164.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	NM_015164.4	MANE Select	c.61-7C>T		splice_region intron	N/A	NP_055979.2
	PLEKHM2	NM_001410755.1		c.61-7C>T		splice_region intron	N/A	NP_001397684.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.61-7C>T		splice_region intron	N/A	ENSP00000364956.3
	PLEKHM2	ENST00000957356.1		c.61-7C>T		splice_region intron	N/A	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.61-7C>T		splice_region intron	N/A	ENSP00000627412.1

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

GnomAD2 exomes AF: 0.00604 AC: 1008 AN: 166832 AF XY: 0.00565

Gnomad AFR exome AF: 0.00994

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00575

Gnomad EAS exome AF: 0.000533

Gnomad FIN exome AF: 0.00492

Gnomad NFE exome AF: 0.00676

Gnomad OTH exome AF: 0.00845

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0102 AC: 220 AN: 21466

American (AMR) AF: 0.00462 AC: 129 AN: 27920

Ashkenazi Jewish (ASJ) AF: 0.00758 AC: 129 AN: 17008

East Asian (EAS) AF: 0.000437 AC: 15 AN: 34360

South Asian (SAS) AF: 0.00951 AC: 582 AN: 61230

European-Finnish (FIN) AF: 0.00470 AC: 147 AN: 31280

Middle Eastern (MID) AF: 0.00860 AC: 31 AN: 3606

European-Non Finnish (NFE) AF: 0.00724 AC: 6243 AN: 862668

Other (OTH) AF: 0.00671 AC: 297 AN: 44290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000707 AC: 27 AN: 38212

American (AMR) AF: 0.000758 AC: 11 AN: 14520

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 5 AN: 3192

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00500 AC: 23 AN: 4596

European-Finnish (FIN) AF: 0.000537 AC: 5 AN: 9314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00177 AC: 110 AN: 62306

Other (OTH) AF: 0.00154 AC: 3 AN: 1954

Alfa AF: 0.107 Hom.: 263

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated Cardiomyopathy, Recessive (1)
-	-	1	not provided (1)
-	-	1	PLEKHM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.8
DANN	Benign	0.61
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs76932674; hg19: chr1-16042725; COSMIC: COSV107487893; COSMIC: COSV107487893;