rs4802905

Variant names:

• chr19-52220842-T-C
• rs4802905
• NM_014225.6:c.1364-137T>C

Variant summary

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

The NM_014225.6(PPP2R1A):​c.1364-137T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,031,006 control chromosomes in the GnomAD database, including 13,322 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 0.19 (3394 hom., cov: 32)
  • Exomes 𝑓: 0.14 (9928 hom.)
• Consequence: PPP2R1A NM_014225.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.123
• Publications: 10 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6	c.1364-137T>C		intron_variant	Intron 11 of 14	ENST00000322088.11	NP_055040.2
PPP2R1A	NM_001363656.2	c.827-137T>C		intron_variant	Intron 11 of 14		NP_001350585.1
PPP2R1A	NR_033500.2	n.1308-137T>C		intron_variant	Intron 10 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.1364-137T>C		intron_variant	Intron 11 of 14	1	NM_014225.6	ENSP00000324804.6

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28457 AN: 151962 Hom.: 3381 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.0983

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.136 AC: 119471 AN: 878926 Hom.: 9928 AF XY: 0.136 AC XY: 60592 AN XY: 445740

African (AFR) AF: 0.335 AC: 6778 AN: 20238

American (AMR) AF: 0.186 AC: 4801 AN: 25818

Ashkenazi Jewish (ASJ) AF: 0.0981 AC: 1646 AN: 16784

East Asian (EAS) AF: 0.355 AC: 12519 AN: 35288

South Asian (SAS) AF: 0.189 AC: 11060 AN: 58484

European-Finnish (FIN) AF: 0.120 AC: 5468 AN: 45632

Middle Eastern (MID) AF: 0.157 AC: 683 AN: 4354

European-Non Finnish (NFE) AF: 0.111 AC: 70389 AN: 632070

Other (OTH) AF: 0.152 AC: 6127 AN: 40258

GnomAD4 genome AF: 0.187 AC: 28514 AN: 152080 Hom.: 3394 Cov.: 32 AF XY: 0.188 AC XY: 13984 AN XY: 74342

African (AFR) AF: 0.334 AC: 13831 AN: 41430

American (AMR) AF: 0.159 AC: 2438 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0983 AC: 341 AN: 3470

East Asian (EAS) AF: 0.314 AC: 1618 AN: 5154

South Asian (SAS) AF: 0.187 AC: 901 AN: 4816

European-Finnish (FIN) AF: 0.120 AC: 1267 AN: 10600

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7651 AN: 67990

Other (OTH) AF: 0.181 AC: 382 AN: 2114

Alfa AF: 0.149 Hom.: 3306

Bravo AF: 0.200

Asia WGS AF: 0.267 AC: 925 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.0
DANN	Benign	0.67
PhyloP100		-0.12
PromoterAI		-0.0072	Neutral
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: rs4802905; hg19: chr19-52724095; COSMIC: COSV59043211; COSMIC: COSV59043211;