chr1-15727314-C-T

Variant names:

• chr1-15727314-C-T
• rs7517033
• NM_015164.4:c.1242C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_015164.4(PLEKHM2):​c.1242C>T​(p.Ile414Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0085 in 1,601,994 control chromosomes in the GnomAD database, including 994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (499 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (495 hom.)
• Consequence: PLEKHM2 NM_015164.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.30
• 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

ENSG00000237938 (HGNC:58402):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-15727314-C-T is Benign according to our data. Variant chr1-15727314-C-T is described in ClinVar as Benign. ClinVar VariationId is 478065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	NM_015164.4	MANE Select	c.1242C>T	p.Ile414Ile	synonymous	Exon 9 of 20	NP_055979.2
	PLEKHM2	NM_001410755.1		c.1182C>T	p.Ile394Ile	synonymous	Exon 8 of 19	NP_001397684.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM2	ENST00000375799.8	TSL:1 MANE Select	c.1242C>T	p.Ile414Ile	synonymous	Exon 9 of 20	ENSP00000364956.3
	PLEKHM2	ENST00000850891.1		c.1281C>T	p.Ile427Ile	synonymous	Exon 9 of 20	ENSP00000520968.1
	PLEKHM2	ENST00000375793.3	TSL:5	c.1182C>T	p.Ile394Ile	synonymous	Exon 8 of 19	ENSP00000364950.2

Frequencies

GnomAD3 genomes AF: 0.0439 AC: 6677 AN: 151950 Hom.: 497 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000778

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0302

GnomAD2 exomes AF: 0.0107 AC: 2382 AN: 222866 AF XY: 0.00823

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.00764

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000965

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000571

Gnomad OTH exome AF: 0.00558

GnomAD4 exome AF: 0.00478 AC: 6930 AN: 1449926 Hom.: 495 Cov.: 33 AF XY: 0.00417 AC XY: 3006 AN XY: 720342

African (AFR) AF: 0.164 AC: 5439 AN: 33266

American (AMR) AF: 0.00880 AC: 381 AN: 43274

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25816

East Asian (EAS) AF: 0.000408 AC: 16 AN: 39176

South Asian (SAS) AF: 0.000498 AC: 42 AN: 84296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51138

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5760

European-Non Finnish (NFE) AF: 0.000275 AC: 305 AN: 1107300

Other (OTH) AF: 0.0111 AC: 667 AN: 59900

GnomAD4 genome AF: 0.0440 AC: 6689 AN: 152068 Hom.: 499 Cov.: 32 AF XY: 0.0422 AC XY: 3138 AN XY: 74334

African (AFR) AF: 0.153 AC: 6354 AN: 41450

American (AMR) AF: 0.0142 AC: 217 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000780 AC: 4 AN: 5128

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67984

Other (OTH) AF: 0.0299 AC: 63 AN: 2108

Alfa AF: 0.0237 Hom.: 159

Bravo AF: 0.0509

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dilated Cardiomyopathy, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.5
DANN	Benign	0.83
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -6

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

Other links and lift over

dbSNP: rs7517033; hg19: chr1-16053809;