rs869320691

chr6-43007292-T-Achr6-43007292-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_006245.4(PPP2R5D):c.619T>A(p.Trp207Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W207C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_006245.4 (PPP2R5D) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 280435
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006245.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-43007294-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1333678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PPP2R5D
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 6-43007292-T-A is Pathogenic according to our data. Variant chr6-43007292-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 217457.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-43007292-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP2R5D	NM_006245.4	c.619T>A	p.Trp207Arg	missense_variant	5/16	ENST00000485511.6
PPP2R5D	NM_180976.3	c.523T>A	p.Trp175Arg	missense_variant	5/16
PPP2R5D	NM_180977.3	c.301T>A	p.Trp101Arg	missense_variant	3/14
PPP2R5D	NM_001270476.2	c.166T>A	p.Trp56Arg	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.619T>A	p.Trp207Arg	missense_variant	5/16	1	NM_006245.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hogue-Janssens syndrome 1 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 03, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.2	H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-13	D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.98
MutPred		0.91		Gain of disorder (P = 0.0026);.;.;.;
MVP		0.86
MPC		3.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.94

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: rs869320691; hg19: chr6-42975030;