6-43007966-G-A

Position:

• chr6-43007966-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_006245.4(PPP2R5D):​c.758G>A​(p.Arg253Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP2R5D. . Gene score misZ 3.6476 (greater than the threshold 3.09). Trascript score misZ 4.9069 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, Hogue-Janssens syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 6-43007966-G-A is Pathogenic according to our data. Variant chr6-43007966-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429222.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.758G>A	p.Arg253Gln	missense_variant	7/16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.662G>A	p.Arg221Gln	missense_variant	7/16		NP_851307.1
PPP2R5D	NM_180977.3	c.440G>A	p.Arg147Gln	missense_variant	5/14		NP_851308.1
PPP2R5D	NM_001270476.2	c.305G>A	p.Arg102Gln	missense_variant	7/16		NP_001257405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.758G>A	p.Arg253Gln	missense_variant	7/16	1	NM_006245.4	ENSP00000417963.1
PPP2R5D	ENST00000394110.7	c.662G>A	p.Arg221Gln	missense_variant	7/16	1		ENSP00000377669.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251494 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461882 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hogue-Janssens syndrome 1 Pathogenic:2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Oct 31, 2017	This 5 year old male has a history of global developmental delay, macrocephaly, hypotonia, vision abnormalities, torticollis, and plagiocephaly. This variant is absent from gnomAD but present in ExAC at a frequency of 0.0008121% overall. Computational models suggest that this variant is probably damaging to protein structure and/or function. The variant was inherited from the patient's father who has a history of dyslexia and who required learning supports in elementary school. Pathogenic de novo missense variants in PPP2R5D have been reported in individuals with intellectual disability, autism spectrum disorder, macrocephaly, hypotonia, increased height, seizures, and dysmorphic features (PMID:25972378; PMID:26576547). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4_Supporting+PM6_Supporting+PM5_Supporting+PP2+PM1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.758G>A in Exon 7 of the PPP2R5D gene that results in the amino acid substitution p.Arg253Gln was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic and Uncertain Significance (variant ID: 429222). This variant has previously been reported for neurodevelopmental disorders (Krgovic D et al., 2022). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 12, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 429222). This variant has not been reported in the literature in individuals affected with PPP2R5D-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 253 of the PPP2R5D protein (p.Arg253Gln). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2024	Reported heterozygous in a patient with autism and intellectual disability in published literature without additional clinical information or familial segregation information (PMID: 35813072, 37167322); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35813072, 36833222, 37167322) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Pathogenic	4.2	H;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.82
MutPred		0.91		Loss of catalytic residue at R253 (P = 0.0336);.;.;.;
MVP		0.87
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.76
gMVP		0.77

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: rs1131691266; hg19: chr6-42975704; COSMIC: COSV55150458; COSMIC: COSV55150458;