19-52212538-G-A

Variant names:

• chr19-52212538-G-A
• rs10403202
• NM_014225.6:c.504-148G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014225.6(PPP2R1A):​c.504-148G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0833 in 952,788 control chromosomes in the GnomAD database, including 3,771 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1118 hom., cov: 32)
  • Exomes 𝑓: 0.078 (2653 hom.)
• Consequence: PPP2R1A NM_014225.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.94
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6	c.504-148G>A		intron_variant	Intron 4 of 14	ENST00000322088.11	NP_055040.2
PPP2R1A	NM_001363656.2	c.-34-148G>A		intron_variant	Intron 4 of 14		NP_001350585.1
PPP2R1A	NR_033500.2	n.448-148G>A		intron_variant	Intron 3 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.504-148G>A		intron_variant	Intron 4 of 14	1	NM_014225.6	ENSP00000324804.6

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16708 AN: 152044 Hom.: 1110 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0631

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0573

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0785

Gnomad OTH AF: 0.0872

GnomAD4 exome AF: 0.0782 AC: 62626 AN: 800626 Hom.: 2653 Cov.: 11 AF XY: 0.0772 AC XY: 31180 AN XY: 403958

African (AFR) AF: 0.187 AC: 3551 AN: 19036

American (AMR) AF: 0.0510 AC: 1139 AN: 22320

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 990 AN: 16448

East Asian (EAS) AF: 0.0911 AC: 2955 AN: 32424

South Asian (SAS) AF: 0.0572 AC: 3135 AN: 54814

European-Finnish (FIN) AF: 0.108 AC: 3305 AN: 30738

Middle Eastern (MID) AF: 0.0659 AC: 178 AN: 2700

European-Non Finnish (NFE) AF: 0.0756 AC: 44204 AN: 584574

Other (OTH) AF: 0.0843 AC: 3169 AN: 37572

GnomAD4 genome AF: 0.110 AC: 16755 AN: 152162 Hom.: 1118 Cov.: 32 AF XY: 0.110 AC XY: 8170 AN XY: 74386

African (AFR) AF: 0.190 AC: 7882 AN: 41500

American (AMR) AF: 0.0632 AC: 966 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 227 AN: 3470

East Asian (EAS) AF: 0.123 AC: 635 AN: 5180

South Asian (SAS) AF: 0.0563 AC: 272 AN: 4832

European-Finnish (FIN) AF: 0.116 AC: 1227 AN: 10572

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0785 AC: 5339 AN: 68004

Other (OTH) AF: 0.0878 AC: 185 AN: 2108

Alfa AF: 0.0864 Hom.: 388

Bravo AF: 0.109

Asia WGS AF: 0.109 AC: 377 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.097
DANN	Benign	0.75
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10403202; hg19: chr19-52715791; COSMIC: COSV59046356; COSMIC: COSV59046356;