2-48454721-C-G

Variant names:

• chr2-48454721-C-G
• rs144842602
• NM_001135629.3:c.253C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001135629.3(PPP1R21):​c.253C>G​(p.Pro85Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P85S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PPP1R21 NM_001135629.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 0 publications found

Genes affected

PPP1R21 (HGNC:30595): (protein phosphatase 1 regulatory subunit 21) Located in early endosome. [provided by Alliance of Genome Resources, Apr 2022]

PPP1R21 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0639562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R21	NM_001135629.3	c.253C>G	p.Pro85Ala	missense_variant	Exon 3 of 22	ENST00000294952.13	NP_001129101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R21	ENST00000294952.13	c.253C>G	p.Pro85Ala	missense_variant	Exon 3 of 22	1	NM_001135629.3	ENSP00000294952.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.27
DEOGEN2	Benign	0.018	.;.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.074
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.00072	T
MetaRNN	Benign	0.064	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;N;N;.
PhyloP100		1.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.050	N;N;N;N
REVEL	Benign	0.084
Sift	Benign	0.51	T;T;T;T
Sift4G	Benign	0.79	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.24
MutPred		0.37		Loss of glycosylation at P85 (P = 0.0386);Loss of glycosylation at P85 (P = 0.0386);Loss of glycosylation at P85 (P = 0.0386);.;
MVP		0.20
MPC		0.010
ClinPred		0.085	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.028
gMVP		0.070
Mutation Taster		=90/10	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: rs144842602; hg19: chr2-48681860;