19-52208067-G-A

Variant names:

• chr19-52208067-G-A
• rs7251605
• NM_014225.6:c.270+2004G>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.270+2004G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 152,170 control chromosomes in the GnomAD database, including 4,382 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 0.23 (4382 hom., cov: 32)
• Consequence: PPP2R1A NM_014225.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• Publications: 8 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 = 0.308 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014225.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	NM_014225.6	MANE Select	c.270+2004G>A		intron	N/A	NP_055040.2
	PPP2R1A	NM_001363656.2		c.-268+2004G>A		intron	N/A	NP_001350585.1
	PPP2R1A	NR_033500.2		n.215-3193G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	ENST00000322088.11	TSL:1 MANE Select	c.270+2004G>A		intron	N/A	ENSP00000324804.6
	PPP2R1A	ENST00000454220.7	TSL:1	c.390+2004G>A		intron	N/A	ENSP00000391905.3
	PPP2R1A	ENST00000703398.1		c.312+2004G>A		intron	N/A	ENSP00000515288.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34900 AN: 152052 Hom.: 4373 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.223

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.230 AC: 34942 AN: 152170 Hom.: 4382 Cov.: 32 AF XY: 0.226 AC XY: 16782 AN XY: 74394

African (AFR) AF: 0.312 AC: 12948 AN: 41500

American (AMR) AF: 0.207 AC: 3172 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 751 AN: 3470

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5180

South Asian (SAS) AF: 0.153 AC: 739 AN: 4822

European-Finnish (FIN) AF: 0.182 AC: 1932 AN: 10590

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14536 AN: 68002

Other (OTH) AF: 0.220 AC: 465 AN: 2112

Alfa AF: 0.217 Hom.: 6971

Bravo AF: 0.236

Asia WGS AF: 0.0820 AC: 289 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		1.6
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: rs7251605; hg19: chr19-52711320;