19-52212959-C-G

Variant names:

• chr19-52212959-C-G
• NM_014225.6:c.656C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_014225.6(PPP2R1A):​c.656C>G​(p.Ser219Trp) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R1A NM_014225.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

Genes affected

PPP2R1A (HGNC:9302): (protein phosphatase 2 scaffold subunit Aalpha) This gene encodes a constant regulatory subunit of protein phosphatase 2. Protein phosphatase 2 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 constant regulatory subunit A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. This gene encodes an alpha isoform of the constant regulatory subunit A. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest SV40 small T antigen binding (size 154) in uniprot entity 2AAA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_014225.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PPP2R1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 4.4565 (above the threshold of 3.09). Trascript score misZ: 5.4176 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, Houge-Janssens syndrome 2, complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6	c.656C>G	p.Ser219Trp	missense_variant	Exon 6 of 15	ENST00000322088.11	NP_055040.2
PPP2R1A	NM_001363656.2	c.119C>G	p.Ser40Trp	missense_variant	Exon 6 of 15		NP_001350585.1
PPP2R1A	NR_033500.2	n.600C>G		non_coding_transcript_exon_variant	Exon 5 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.656C>G	p.Ser219Trp	missense_variant	Exon 6 of 15	1	NM_014225.6	ENSP00000324804.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Houge-Janssens syndrome 2 Uncertain:1

May 13, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Ser219Trp variant in PPP2R1A was identified by our study, in 1 individual with Houge-Janssens syndrome 2. Trio exome analysis showed this variant to be de novo. This variant has not been previously reported in individuals with Houge-Janssens syndrome 2 and was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional likely pathogenic/pathogenic variant, resulting in a different amino acid change at the same position, (p.Ser219Leu), has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 521503). In summary, the clinical significance of the (p.Ser219Trp) variant is uncertain. ACMG/AMP Criteria applied: PS2_Supporting, PM2_Supporting, PM5 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	4.0	H;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D;.;.
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.59
MutPred		0.76		Loss of disorder (P = 0.0028);.;.;
MVP		0.80
MPC		3.1
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-52716212; COSMIC: COSV59042459; COSMIC: COSV59042459;