1-15684398-C-T

Variant names:

• chr1-15684398-C-T
• rs868468787
• NM_015164.4:c.-161C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_015164.4(PLEKHM2):​c.-161C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 203,812 control chromosomes in the GnomAD database, including 371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (364 hom., cov: 28)
  • Exomes 𝑓: 0.0031 (7 hom.)
• Consequence: PLEKHM2 NM_015164.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.476
• 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: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-15684398-C-T is Benign according to our data. Variant chr1-15684398-C-T is described in ClinVar as Benign. ClinVar VariationId is 1223527.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

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.-161C>T		5_prime_UTR	Exon 1 of 20	NP_055979.2	Q8IWE5-1
	PLEKHM2	NM_001410755.1		c.-161C>T		5_prime_UTR	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.-161C>T		5_prime_UTR	Exon 1 of 20	ENSP00000364956.3	Q8IWE5-1
	PLEKHM2	ENST00000957353.1		c.-161C>T		5_prime_UTR	Exon 1 of 20	ENSP00000627412.1
	PLEKHM2	ENST00000957355.1		c.-161C>T		5_prime_UTR	Exon 1 of 20	ENSP00000627414.1

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5626 AN: 144586 Hom.: 363 Cov.: 28

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000424

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.000629

Gnomad OTH AF: 0.0371

GnomAD4 exome AF: 0.00308 AC: 182 AN: 59134 Hom.: 7 Cov.: 3 AF XY: 0.00258 AC XY: 73 AN XY: 28254

African (AFR) AF: 0.119 AC: 152 AN: 1272

American (AMR) AF: 0.0122 AC: 1 AN: 82

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 346

East Asian (EAS) AF: 0.00 AC: 0 AN: 260

South Asian (SAS) AF: 0.00 AC: 0 AN: 1250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16

Middle Eastern (MID) AF: 0.00926 AC: 1 AN: 108

European-Non Finnish (NFE) AF: 0.000260 AC: 14 AN: 53840

Other (OTH) AF: 0.00714 AC: 14 AN: 1960

GnomAD4 genome AF: 0.0390 AC: 5643 AN: 144678 Hom.: 364 Cov.: 28 AF XY: 0.0370 AC XY: 2601 AN XY: 70346

African (AFR) AF: 0.130 AC: 5241 AN: 40404

American (AMR) AF: 0.0193 AC: 284 AN: 14692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 4838

South Asian (SAS) AF: 0.000424 AC: 2 AN: 4716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8272

Middle Eastern (MID) AF: 0.00362 AC: 1 AN: 276

European-Non Finnish (NFE) AF: 0.000629 AC: 41 AN: 65178

Other (OTH) AF: 0.0367 AC: 74 AN: 2014

Alfa AF: 0.00714 Hom.: 4

Bravo AF: 0.0434

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.94
PhyloP100		-0.48
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=296/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs868468787; hg19: chr1-16010893;