chr11-111743383-C-G

Variant names:

• chr11-111743383-C-G
• rs758785850
• NM_002716.5:c.1547G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002716.5(PPP2R1B):​c.1547G>C​(p.Cys516Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C516Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PPP2R1B NM_002716.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.76
• Publications: 0 publications found

Genes affected

PPP2R1B (HGNC:9303): (protein phosphatase 2 scaffold subunit Abeta) 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 a beta isoform of the constant regulatory subunit A. Mutations in this gene have been associated with some lung and colon cancers. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002716.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1B	NM_002716.5	MANE Select	c.1547G>C	p.Cys516Ser	missense	Exon 12 of 15	NP_002707.3
	PPP2R1B	NM_181699.3		c.1547G>C	p.Cys516Ser	missense	Exon 12 of 16	NP_859050.1	P30154-2
	PPP2R1B	NM_181700.2		c.1355G>C	p.Cys452Ser	missense	Exon 10 of 14	NP_859051.1	P30154-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1B	ENST00000527614.6	TSL:1 MANE Select	c.1547G>C	p.Cys516Ser	missense	Exon 12 of 15	ENSP00000437193.1	P30154-1
	PPP2R1B	ENST00000311129.9	TSL:1	c.1547G>C	p.Cys516Ser	missense	Exon 12 of 16	ENSP00000311344.5	P30154-2
	PPP2R1B	ENST00000426998.6	TSL:2	c.1355G>C	p.Cys452Ser	missense	Exon 10 of 14	ENSP00000410671.2	P30154-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453368 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000302 AC: 1 AN: 33098

American (AMR) AF: 0.00 AC: 0 AN: 43496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106930

Other (OTH) AF: 0.00 AC: 0 AN: 60058

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.21
Sift	Benign	0.11	T
Sift4G	Benign	0.25	T
Polyphen		0.038	B
Vest4		0.78
MutPred		0.67		Loss of stability (P = 0.0796)
MVP		0.51
MPC		0.27
ClinPred		0.82	D
GERP RS		5.9
Varity_R		0.39
gMVP		0.62
Mutation Taster		=68/32	polymorphism

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: rs758785850; hg19: chr11-111614107;