1-15684608-C-A

Variant names:

• chr1-15684608-C-A
• NM_015164.4:c.50C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015164.4(PLEKHM2):​c.50C>A​(p.Ser17*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000861 in 1,161,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S17S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.50C>A	p.Ser17*	stop_gained	Exon 1 of 20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1	c.50C>A	p.Ser17*	stop_gained	Exon 1 of 19		NP_001397684.1
PLEKHM2	XM_017000757.1	c.99+2909C>A		intron_variant	Intron 1 of 19		XP_016856246.1
PLEKHM2	XM_017000758.1	c.99+2909C>A		intron_variant	Intron 1 of 18		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.50C>A	p.Ser17*	stop_gained	Exon 1 of 20	1	NM_015164.4	ENSP00000364956.3
PLEKHM2	ENST00000375793.2	c.50C>A	p.Ser17*	stop_gained	Exon 1 of 19	5		ENSP00000364950.2
PLEKHM2	ENST00000642363.1	c.50C>A	p.Ser17*	stop_gained	Exon 1 of 21			ENSP00000494591.1
PLEKHM2	ENST00000462455.1	n.68C>A		non_coding_transcript_exon_variant	Exon 1 of 5	5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 8.61e-7 AC: 1 AN: 1161028 Hom.: 0 Cov.: 30 AF XY: 0.00000176 AC XY: 1 AN XY: 566584

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000268

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.26	N
Vest4		0.064
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: -3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-16011103;