1-15733848-G-C

Variant names:

• chr1-15733848-G-C
• rs369250576
• NM_015164.4:c.2974G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015164.4(PLEKHM2):​c.2974G>C​(p.Glu992Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E992K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PLEKHM2 NM_015164.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.26

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]

ENSG00000237938 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15950334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHM2	NM_015164.4	c.2974G>C	p.Glu992Gln	missense_variant	Exon 20 of 20	ENST00000375799.8	NP_055979.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHM2	ENST00000375799.8	c.2974G>C	p.Glu992Gln	missense_variant	Exon 20 of 20	1	NM_015164.4	ENSP00000364956.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460794 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726704

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.043
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.30	N;N;.
REVEL	Benign	0.048
Sift	Benign	0.14	T;T;.
Sift4G	Benign	0.25	T;T;.
Polyphen		0.15	B;.;.
Vest4		0.21
MutPred		0.14		Gain of MoRF binding (P = 0.0432);.;.;
MVP		0.43
MPC		0.33
ClinPred		0.68	D
GERP RS		4.7
Varity_R		0.15
gMVP		0.24

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: rs369250576; hg19: chr1-16060343;