chr1-15715894-T-C

Position:

• chr1-15715894-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015164.4(PLEKHM2):​c.61-343T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,184 control chromosomes in the GnomAD database, including 4,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.22 (4251 hom., cov: 33)
• Consequence: PLEKHM2 NM_015164.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0860

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-15715894-T-C is Benign according to our data. Variant chr1-15715894-T-C is described in ClinVar as [Benign]. Clinvar id is 1230141.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM2	NM_015164.4	c.61-343T>C		intron_variant		ENST00000375799.8
PLEKHM2	NM_001410755.1	c.61-343T>C		intron_variant
PLEKHM2	XM_017000757.1	c.100-343T>C		intron_variant
PLEKHM2	XM_017000758.1	c.100-343T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.61-343T>C		intron_variant		1	NM_015164.4	P2
PLEKHM2	ENST00000375793.2	c.61-343T>C		intron_variant		5		A2
PLEKHM2	ENST00000642363.1	c.61-343T>C		intron_variant				A2
PLEKHM2	ENST00000462455.1	n.79-343T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33655 AN: 152066 Hom.: 4243 Cov.: 33

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.0308

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.229

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.221 AC: 33701 AN: 152184 Hom.: 4251 Cov.: 33 AF XY: 0.217 AC XY: 16143 AN XY: 74400

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.0307

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.181

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.232

Alfa AF: 0.208 Hom.: 435

Bravo AF: 0.223

Asia WGS AF: 0.124 AC: 430 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs34859842; hg19: chr1-16042389;