rs863225082

Variant names:

• chr6-43007265-G-A
• rs863225082
• NM_006245.4:c.592G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-43007265-G-A
• chr6-43007265-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_006245.4(PPP2R5D):​c.592G>A​(p.Glu198Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000920080: demonstrating loss of binding to the catalytic subunit, which leads to a defect in PP2A-B56delta-dependent dephosphorylation activity (Houge 2015)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:31 O:1
• Conservation: PhyloP100: 10.0
• Publications: 46 publications found

Genes affected

PPP2R5D (HGNC:9312): (protein phosphatase 2 regulatory subunit B'delta) The product of this gene belongs to the phosphatase 2A regulatory subunit B family. Protein phosphatase 2A is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a delta isoform of the regulatory subunit B56 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

PPP2R5D Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Hogue-Janssens syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000920080: demonstrating loss of binding to the catalytic subunit, which leads to a defect in PP2A-B56delta-dependent dephosphorylation activity (Houge 2015).; SCV000996151: Functional analysis of cells expressing the p.Glu298Lys variant showed deficient PP2A holoenzyme formation (PMID: 26168268).; SCV002506802: "In vitro functional studies showed that the p.Glu298Lys variant results in deficient PP2A holoenzyme formation." PMID: 26168268; SCV000256081: Published functional studies using HEK293 cells transfected with this variant demonstrate deficient holoenzyme formation (Houge et al., 2015); PMID: 28554332, 29595814, 26168268, 25533962, 26576547, 25972378, 29288388, 28628100, 28867141, 28135719, 29051493, 29346770, 29296277, 28191890, 31036916, 32156701, 31019026, 31981491, 33338668, 32959227, 33084218, 33098801; SCV001583441: Experimental studies have shown that this missense change affects PPP2R5D function (PMID: 26168268).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_006245.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 6-43007265-G-A is Pathogenic according to our data. Variant chr6-43007265-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 190286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R5D	NM_006245.4	MANE Select	c.592G>A	p.Glu198Lys	missense	Exon 5 of 16	NP_006236.1	Q14738-1
	PPP2R5D	NM_180976.3		c.496G>A	p.Glu166Lys	missense	Exon 5 of 16	NP_851307.1	Q14738-2
	PPP2R5D	NM_180977.3		c.274G>A	p.Glu92Lys	missense	Exon 3 of 14	NP_851308.1	Q14738-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R5D	ENST00000485511.6	TSL:1 MANE Select	c.592G>A	p.Glu198Lys	missense	Exon 5 of 16	ENSP00000417963.1	Q14738-1
	PPP2R5D	ENST00000394110.7	TSL:1	c.496G>A	p.Glu166Lys	missense	Exon 5 of 16	ENSP00000377669.3	Q14738-2
	PPP2R5D	ENST00000470467.5	TSL:1	c.349G>A	p.Glu117Lys	missense	Exon 3 of 13	ENSP00000419756.1	H0Y8C4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
19	-	-	Hogue-Janssens syndrome 1 (20)
7	-	-	not provided (7)
1	-	-	Global developmental delay (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	Neurodevelopmental delay (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.67		Gain of ubiquitination at E198 (P = 0.0048)
MVP		0.85
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.86
gMVP		0.67
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863225082; hg19: chr6-42975003; COSMIC: COSV55150326; COSMIC: COSV55150326;