NM_006245.4:c.598G>A

Variant names:

• chr6-43007271-G-A
• rs863225079
• NM_006245.4:c.598G>A

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.598G>A​(p.Glu200Lys) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001427093: "functional studies suggest the p.Glu200Lys variant reduces binding to other protein phosphatase 2A subunits (Houge et al., 2015)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E200Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: 9.95
• Publications: 30 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: SCV001427093: "functional studies suggest the p.Glu200Lys variant reduces binding to other protein phosphatase 2A subunits (Houge et al., 2015)."; SCV004241146: Functional studies report experimental evidence evaluating an impact on protein function and this variant affects PPP2R5D protein function (Houge_2015, Oyama_2022). PMID: 32005694, 26168268, 25972378, 29051493, 36216457; SCV005088760: Functional studies suggested that this variant reduces binding to other protein phosphatase 2A subunits [PMID: 26168268].; SCV000256078: Published functional studies demonstrate a damaging effect: deficient holoenzyme formation with some residual binding capability in vitro (Houge et al., 2015); PMID:26576547
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_006245.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 6-43007271-G-A is Pathogenic according to our data. Variant chr6-43007271-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217456.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.598G>A	p.Glu200Lys	missense	Exon 5 of 16	NP_006236.1	Q14738-1
	PPP2R5D	NM_180976.3		c.502G>A	p.Glu168Lys	missense	Exon 5 of 16	NP_851307.1	Q14738-2
	PPP2R5D	NM_180977.3		c.280G>A	p.Glu94Lys	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.598G>A	p.Glu200Lys	missense	Exon 5 of 16	ENSP00000417963.1	Q14738-1
	PPP2R5D	ENST00000394110.7	TSL:1	c.502G>A	p.Glu168Lys	missense	Exon 5 of 16	ENSP00000377669.3	Q14738-2
	PPP2R5D	ENST00000470467.5	TSL:1	c.355G>A	p.Glu119Lys	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/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Hogue-Janssens syndrome 1 (14)
9	-	-	not provided (9)
1	-	-	Inborn genetic diseases (1)
1	-	-	PPP2R5D-related disorder (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	0.27
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		10
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.92
MutPred		0.73		Gain of ubiquitination at E200 (P = 0.0121)
MVP		0.83
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.78
gMVP		0.69
Mutation Taster		=0/100	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: rs863225079; hg19: chr6-42975009;