2-28752155-C-T

Variant names:

• chr2-28752155-C-T
• rs960710587
• NM_002709.3:c.31C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002709.3(PPP1CB):​c.31C>T​(p.Leu11Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,396,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. L11V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PPP1CB NM_002709.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25
• Publications: 0 publications found

Genes affected

PPP1CB (HGNC:9282): (protein phosphatase 1 catalytic subunit beta) The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Mouse studies suggest that PP1 functions as a suppressor of learning and memory. Two alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

PPP1CB Gene-Disease associations (from GenCC):

• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome-like disorder with loose anagen hair 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37566495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1CB	NM_002709.3	c.31C>T	p.Leu11Phe	missense_variant	Exon 1 of 8	ENST00000395366.3	NP_002700.1
PPP1CB	NM_206876.2	c.31C>T	p.Leu11Phe	missense_variant	Exon 2 of 9		NP_996759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3	c.31C>T	p.Leu11Phe	missense_variant	Exon 1 of 8	1	NM_002709.3	ENSP00000378769.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1396272 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 688684

African (AFR) AF: 0.00 AC: 0 AN: 31082

American (AMR) AF: 0.00 AC: 0 AN: 35622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25084

East Asian (EAS) AF: 0.00 AC: 0 AN: 35254

South Asian (SAS) AF: 0.00 AC: 0 AN: 79208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1077526

Other (OTH) AF: 0.00 AC: 0 AN: 57872

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	.;T;T;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.87	D;D;D;.;.
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.5	.;.;M;M;M
PhyloP100		2.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Benign	0.081	T;T;T;T;T
Polyphen		0.65	.;.;P;P;P
Vest4		0.28, 0.28, 0.27
MutPred		0.47		Loss of disorder (P = 0.2201);Loss of disorder (P = 0.2201);Loss of disorder (P = 0.2201);Loss of disorder (P = 0.2201);Loss of disorder (P = 0.2201);
MVP		0.45
MPC		1.8
ClinPred		0.98	D
GERP RS		4.7
PromoterAI		-0.11	Neutral
Varity_R		0.56
gMVP		0.97
Mutation Taster		=34/66	disease causing

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: rs960710587; hg19: chr2-28975021;