15-64864975-C-A

Position:

• chr15-64864975-C-A

Variant summary

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

The NM_025201.5(PLEKHO2):​c.560C>A​(p.Pro187His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLEKHO2 NM_025201.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

Genes affected

PLEKHO2 (HGNC:30026): (pleckstrin homology domain containing O2) Predicted to act upstream of or within macrophage apoptotic process. Predicted to be located in extracellular region and ficolin-1-rich granule lumen. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000249240 (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=0.20962596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHO2	NM_025201.5	c.560C>A	p.Pro187His	missense_variant	6/6	ENST00000323544.5	NP_079477.2
PLEKHO2	NM_001195059.2	c.410C>A	p.Pro137His	missense_variant	5/5		NP_001181988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHO2	ENST00000323544.5	c.560C>A	p.Pro187His	missense_variant	6/6	1	NM_025201.5	ENSP00000326706.4
PLEKHO2	ENST00000616065.4	c.410C>A	p.Pro137His	missense_variant	5/5	1		ENSP00000483505.1
ENSG00000249240	ENST00000437723.1	c.483+3400C>A		intron_variant		5		ENSP00000397942.1
ENSG00000249240	ENST00000502574.1	n.617+3400C>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.560C>A (p.P187H) alteration is located in exon 6 (coding exon 6) of the PLEKHO2 gene. This alteration results from a C to A substitution at nucleotide position 560, causing the proline (P) at amino acid position 187 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0043	.;T
Eigen	Benign	0.052
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.025	D;D
Polyphen		1.0	D;D
Vest4		0.24
MutPred		0.20		.;Gain of catalytic residue at P187 (P = 0.0393);
MVP		0.52
MPC		0.48
ClinPred		0.86	D
GERP RS		5.6
Varity_R		0.18
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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: chr15-65157174;