15-64859916-C-G

Position:

• chr15-64859916-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_025201.5(PLEKHO2):​c.302C>G​(p.Ala101Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 4.74

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHO2	NM_025201.5	c.302C>G	p.Ala101Gly	missense_variant	4/6	ENST00000323544.5	NP_079477.2
PLEKHO2	NM_001195059.2	c.152C>G	p.Ala51Gly	missense_variant	3/5		NP_001181988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHO2	ENST00000323544.5	c.302C>G	p.Ala101Gly	missense_variant	4/6	1	NM_025201.5	ENSP00000326706.4
PLEKHO2	ENST00000616065.4	c.152C>G	p.Ala51Gly	missense_variant	3/5	1		ENSP00000483505.1
ENSG00000249240	ENST00000437723.1	c.302C>G	p.Ala101Gly	missense_variant	4/7	5		ENSP00000397942.1
ENSG00000249240	ENST00000502574.1	n.436C>G		non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Feb 03, 2022

The c.302C>G (p.A101G) alteration is located in exon 4 (coding exon 4) of the PLEKHO2 gene. This alteration results from a C to G substitution at nucleotide position 302, causing the alanine (A) at amino acid position 101 to be replaced by a glycine (G). 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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.8	.;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0060	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.67
MutPred		0.81		.;Loss of stability (P = 0.0646);Loss of stability (P = 0.0646);
MVP		0.85
MPC		0.51
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.57
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-65152115;