2-48458137-A-C

Variant names:

• chr2-48458137-A-C
• rs141303876
• NM_001135629.3:c.285A>C

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.285A>C​(p.Glu95Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,316 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. Synonymous variant affecting the same amino acid position (i.e. E95E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PPP1R21 NM_001135629.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.775
• 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=0.04828942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R21	NM_001135629.3	c.285A>C	p.Glu95Asp	missense_variant	Exon 4 of 22	ENST00000294952.13	NP_001129101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R21	ENST00000294952.13	c.285A>C	p.Glu95Asp	missense_variant	Exon 4 of 22	1	NM_001135629.3	ENSP00000294952.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457316 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725214

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 86076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108518

Other (OTH) AF: 0.0000166 AC: 1 AN: 60208

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.9
DANN	Benign	0.91
DEOGEN2	Benign	0.018	.;.;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N;N;N
PhyloP100		0.78
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.28	N;N;N
REVEL	Benign	0.039
Sift	Benign	0.56	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.016	B;.;B
Vest4		0.27
MutPred		0.31		Loss of methylation at K92 (P = 0.0938);Loss of methylation at K92 (P = 0.0938);Loss of methylation at K92 (P = 0.0938);
MVP		0.19
MPC		0.011
ClinPred		0.065	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.043
gMVP		0.066
Mutation Taster		=94/6	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: rs141303876; hg19: chr2-48685276;