chr14-35095164-T-C

Variant names:

• chr14-35095164-T-C
• NM_017917.4:c.859A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017917.4(PPP2R3C):​c.859A>G​(p.Lys287Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PPP2R3C NM_017917.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90
• Publications: 0 publications found

Genes affected

PPP2R3C (HGNC:17485): (protein phosphatase 2 regulatory subunit B''gamma) This gene encodes a regulatory subunit of the serine/threonine phosphatase, protein phosphatase 2. This protein is localized to both nuclear and cytoplasmic regions depending on cell cycle phase. Homozygous conditional knockout mice for this gene exhibit reduced numbers and impaired proliferation of immune system B cells. This protein may regulate the expression of the P-glycoprotein ATP-binding cassette transporter through its phosphatase activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

FAM177A1 (HGNC:19829): (family with sequence similarity 177 member A1) This gene encodes a member of a conserved protein family. Alternative splicing results in multiple transcript variants. This gene is thought to be associated with susceptibility to juvenile idiopathic arthritis. [provided by RefSeq, Apr 2017]

FAM177A1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, G2P

LOC101927178 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017917.4. 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
	PPP2R3C	NM_017917.4	MANE Select	c.859A>G	p.Lys287Glu	missense	Exon 10 of 13	NP_060387.2
	PPP2R3C	NM_001305155.2		c.529A>G	p.Lys177Glu	missense	Exon 9 of 12	NP_001292084.1	Q969Q6-2
	PPP2R3C	NM_001305156.2		c.529A>G	p.Lys177Glu	missense	Exon 10 of 13	NP_001292085.1	Q969Q6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R3C	ENST00000261475.10	TSL:1 MANE Select	c.859A>G	p.Lys287Glu	missense	Exon 10 of 13	ENSP00000261475.5	Q969Q6-1
	PPP2R3C	ENST00000557217.5	TSL:1	n.*662A>G		non_coding_transcript_exon	Exon 9 of 12	ENSP00000452436.1	G3V228
	PPP2R3C	ENST00000557217.5	TSL:1	n.*662A>G		3_prime_UTR	Exon 9 of 12	ENSP00000452436.1	G3V228

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.33
Sift	Benign	0.18	T
Sift4G	Benign	0.65	T
Polyphen		0.029	B
Vest4		0.86
MutPred		0.35		Loss of ubiquitination at K287 (P = 0.0092)
MVP		0.72
MPC		0.60
ClinPred		0.89	D
GERP RS		5.3
PromoterAI		0.012	Neutral
Varity_R		0.31
gMVP		0.64
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

hg19: chr14-35564370;