rs34109536

Variant names:

• chr8-26366341-C-T
• rs34109536
• NM_002717.4:c.999C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002717.4(PPP2R2A):​c.999C>T​(p.Leu333Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.041 in 1,603,544 control chromosomes in the GnomAD database, including 1,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (85 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1453 hom.)
• Consequence: PPP2R2A NM_002717.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.901
• Publications: 5 publications found

Genes affected

PPP2R2A (HGNC:9304): (protein phosphatase 2 regulatory subunit Balpha) The product of this gene belongs to the phosphatase 2 regulatory subunit B family. 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 B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes an alpha isoform of the regulatory subunit B55 subfamily. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 8-26366341-C-T is Benign according to our data. Variant chr8-26366341-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1679069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.901 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002717.4. 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
	PPP2R2A	NM_002717.4	MANE Select	c.999C>T	p.Leu333Leu	synonymous	Exon 9 of 10	NP_002708.1
	PPP2R2A	NM_001177591.2		c.1029C>T	p.Leu343Leu	synonymous	Exon 9 of 10	NP_001171062.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R2A	ENST00000380737.8	TSL:1 MANE Select	c.999C>T	p.Leu333Leu	synonymous	Exon 9 of 10	ENSP00000370113.3
	PPP2R2A	ENST00000315985.7	TSL:2	c.1029C>T	p.Leu343Leu	synonymous	Exon 9 of 10	ENSP00000325074.7
	PPP2R2A	ENST00000665949.1		c.678C>T	p.Leu226Leu	synonymous	Exon 11 of 12	ENSP00000499648.1

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4667 AN: 152004 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0341

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.0305

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0449

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0338 AC: 8234 AN: 243542 AF XY: 0.0349

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.0375

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.0426

Gnomad OTH exome AF: 0.0417

GnomAD4 exome AF: 0.0421 AC: 61141 AN: 1451422 Hom.: 1453 Cov.: 30 AF XY: 0.0420 AC XY: 30293 AN XY: 721714

African (AFR) AF: 0.00705 AC: 232 AN: 32896

American (AMR) AF: 0.0399 AC: 1706 AN: 42738

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 898 AN: 25978

East Asian (EAS) AF: 0.00153 AC: 60 AN: 39194

South Asian (SAS) AF: 0.0334 AC: 2790 AN: 83624

European-Finnish (FIN) AF: 0.0258 AC: 1371 AN: 53236

Middle Eastern (MID) AF: 0.0643 AC: 369 AN: 5736

European-Non Finnish (NFE) AF: 0.0462 AC: 51174 AN: 1107990

Other (OTH) AF: 0.0423 AC: 2541 AN: 60030

GnomAD4 genome AF: 0.0307 AC: 4671 AN: 152122 Hom.: 85 Cov.: 32 AF XY: 0.0303 AC XY: 2252 AN XY: 74376

African (AFR) AF: 0.00860 AC: 357 AN: 41520

American (AMR) AF: 0.0340 AC: 520 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3470

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5184

South Asian (SAS) AF: 0.0307 AC: 148 AN: 4820

European-Finnish (FIN) AF: 0.0254 AC: 269 AN: 10572

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0449 AC: 3049 AN: 67950

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

Alfa AF: 0.0410 Hom.: 253

Bravo AF: 0.0320

Asia WGS AF: 0.0210 AC: 73 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.3
DANN	Benign	0.69
PhyloP100		0.90
Mutation Taster		=88/12	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: rs34109536; hg19: chr8-26223857;