rs2016457

Variant names:

• chr19-52215631-T-A
• rs2016457
• NM_014225.6:c.808-148T>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.808-148T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 648,794 control chromosomes in the GnomAD database, including 21,473 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 0.29 (6856 hom., cov: 32)
  • Exomes 𝑓: 0.23 (14617 hom.)
• Consequence: PPP2R1A NM_014225.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6	c.808-148T>A		intron_variant	Intron 6 of 14	ENST00000322088.11	NP_055040.2
PPP2R1A	NM_001363656.2	c.271-148T>A		intron_variant	Intron 6 of 14		NP_001350585.1
PPP2R1A	NR_033500.2	n.752-148T>A		intron_variant	Intron 5 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.808-148T>A		intron_variant	Intron 6 of 14	1	NM_014225.6	ENSP00000324804.6

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43704 AN: 151876 Hom.: 6839 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.232 AC: 115350 AN: 496800 Hom.: 14617 AF XY: 0.228 AC XY: 59468 AN XY: 260602

African (AFR) AF: 0.423 AC: 5660 AN: 13382

American (AMR) AF: 0.202 AC: 4076 AN: 20228

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 3960 AN: 14104

East Asian (EAS) AF: 0.0794 AC: 2473 AN: 31134

South Asian (SAS) AF: 0.143 AC: 6757 AN: 47380

European-Finnish (FIN) AF: 0.272 AC: 9425 AN: 34612

Middle Eastern (MID) AF: 0.270 AC: 552 AN: 2044

European-Non Finnish (NFE) AF: 0.247 AC: 75629 AN: 306416

Other (OTH) AF: 0.248 AC: 6818 AN: 27500

GnomAD4 genome AF: 0.288 AC: 43779 AN: 151994 Hom.: 6856 Cov.: 32 AF XY: 0.285 AC XY: 21146 AN XY: 74290

African (AFR) AF: 0.417 AC: 17279 AN: 41454

American (AMR) AF: 0.217 AC: 3315 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 990 AN: 3470

East Asian (EAS) AF: 0.117 AC: 604 AN: 5146

South Asian (SAS) AF: 0.136 AC: 655 AN: 4818

European-Finnish (FIN) AF: 0.288 AC: 3038 AN: 10560

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17044 AN: 67946

Other (OTH) AF: 0.273 AC: 576 AN: 2112

Alfa AF: 0.272 Hom.: 730

Bravo AF: 0.290

Asia WGS AF: 0.163 AC: 569 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.22
DANN	Benign	0.50
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2016457; hg19: chr19-52718884;