6-43007292-T-C

Variant names:

• chr6-43007292-T-C
• rs869320691
• NM_006245.4:c.619T>C

Variant summary

Our verdict is Pathogenic. The variant received 30 ACMG points: 30P and 0B. PS1_Very_Strong PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006245.4(PPP2R5D):​c.619T>C​(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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004293638: Experimental studies have shown that this missense change affects PPP2R5D function (PMID:26168268)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W207S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 8.02
• Publications: 14 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 30 ACMG points.

• PS1: Transcript NM_006245.4 (PPP2R5D) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004293638: Experimental studies have shown that this missense change affects PPP2R5D function (PMID: 26168268).; SCV004563725: Functional analyses of the p.Trw207Arg variant protein demonstrate impaired subunit binding (Houge 2015). 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, 6 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 chr6-43007293-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1686094.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 6-43007292-T-C is Pathogenic according to our data. Variant chr6-43007292-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280435.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.619T>C	p.Trp207Arg	missense	Exon 5 of 16	NP_006236.1	Q14738-1
	PPP2R5D	NM_180976.3		c.523T>C	p.Trp175Arg	missense	Exon 5 of 16	NP_851307.1	Q14738-2
	PPP2R5D	NM_180977.3		c.301T>C	p.Trp101Arg	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.619T>C	p.Trp207Arg	missense	Exon 5 of 16	ENSP00000417963.1	Q14738-1
	PPP2R5D	ENST00000394110.7	TSL:1	c.523T>C	p.Trp175Arg	missense	Exon 5 of 16	ENSP00000377669.3	Q14738-2
	PPP2R5D	ENST00000470467.5	TSL:1	c.376T>C	p.Trp126Arg	missense	Exon 3 of 13	ENSP00000419756.1	H0Y8C4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Hogue-Janssens syndrome 1 (7)
4	-	-	not provided (4)
1	-	-	Genetic developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.91		Gain of disorder (P = 0.0026)
MVP		0.88
MPC		3.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869320691; hg19: chr6-42975030;