1-15684588-C-T

Variant names:

• chr1-15684588-C-T
• rs780010080
• NM_015164.4:c.30C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_015164.4(PLEKHM2):​c.30C>T​(p.Ile10Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,313,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.505
• Publications: 0 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: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-15684588-C-T is Benign according to our data. Variant chr1-15684588-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1540450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.505 with no splicing effect.

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.30C>T	p.Ile10Ile	synonymous	Exon 1 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.30C>T	p.Ile10Ile	synonymous	Exon 1 of 19	NP_001397684.1	Q8IWE5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.30C>T	p.Ile10Ile	synonymous	Exon 1 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957356.1		c.30C>T	p.Ile10Ile	synonymous	Exon 1 of 21	ENSP00000627415.1
	PLEKHM2	ENST00000957353.1		c.30C>T	p.Ile10Ile	synonymous	Exon 1 of 20	ENSP00000627412.1

Frequencies

GnomAD3 genomes AF: 0.0000867 AC: 13 AN: 149968 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000297 AC: 4 AN: 134826 AF XY: 0.00

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000305

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000602 AC: 7 AN: 1163244 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 568154

African (AFR) AF: 0.000209 AC: 5 AN: 23920

American (AMR) AF: 0.00 AC: 0 AN: 20718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16622

East Asian (EAS) AF: 0.00 AC: 0 AN: 25166

South Asian (SAS) AF: 0.00 AC: 0 AN: 38786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4432

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 950762

Other (OTH) AF: 0.0000226 AC: 1 AN: 44196

GnomAD4 genome AF: 0.0000867 AC: 13 AN: 149968 Hom.: 0 Cov.: 30 AF XY: 0.000123 AC XY: 9 AN XY: 73190

African (AFR) AF: 0.000243 AC: 10 AN: 41104

American (AMR) AF: 0.000199 AC: 3 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5032

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67356

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000125

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Uncertain	0.99
PhyloP100		0.51
PromoterAI		-0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs780010080; hg19: chr1-16011083;