chr19-52190287-C-A

Variant names:

• chr19-52190287-C-A
• rs41275796
• ENST00000454220.7:c.191C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000454220.7(PPP2R1A):​c.191C>A​(p.Pro64Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000093 in 1,075,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P64L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: PPP2R1A ENST00000454220.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.72
• Publications: 0 publications found

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]

PPP2R1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Houge-Janssens syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2930379).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000454220.7. 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
	PPP2R1A	NM_014225.6	MANE Select	c.78+113C>A		intron	N/A	NP_055040.2
	PPP2R1A	NR_033500.2		n.123+113C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	ENST00000454220.7	TSL:1	c.191C>A	p.Pro64Gln	missense	Exon 1 of 15	ENSP00000391905.3
	PPP2R1A	ENST00000322088.11	TSL:1 MANE Select	c.78+113C>A		intron	N/A	ENSP00000324804.6
	PPP2R1A	ENST00000703398.1		c.78+113C>A		intron	N/A	ENSP00000515288.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.30e-7 AC: 1 AN: 1075792 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 537584

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24410

American (AMR) AF: 0.00 AC: 0 AN: 28860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20010

East Asian (EAS) AF: 0.00 AC: 0 AN: 33558

South Asian (SAS) AF: 0.00 AC: 0 AN: 67588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4230

European-Non Finnish (NFE) AF: 0.00000124 AC: 1 AN: 803944

Other (OTH) AF: 0.00 AC: 0 AN: 46784

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.97
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.50	T
PhyloP100		3.7
PROVEAN	Benign	0.020	N
REVEL	Benign	0.20
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
MutPred		0.22		Loss of glycosylation at P64 (P = 0.0322)
MVP		0.49
ClinPred		0.80	D
GERP RS		5.0
PromoterAI		0.033	Neutral
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs41275796; hg19: chr19-52693540;