NM_001135629.3:c.231A>C

Variant names:

• chr2-48454699-A-C
• rs143067822
• NM_001135629.3:c.231A>C

Variant summary

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

The NM_001135629.3(PPP1R21):​c.231A>C​(p.Gln77His) 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 1,461,834 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. Synonymous variant affecting the same amino acid position (i.e. Q77Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PPP1R21 NM_001135629.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.206
• 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: 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, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R21	NM_001135629.3	c.231A>C	p.Gln77His	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.231A>C	p.Gln77His	missense_variant	Exon 3 of 22	1	NM_001135629.3	ENSP00000294952.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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: 0.00000180 AC: 2 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;.;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.0	M;M;M;.
PhyloP100		0.21
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.94
MutPred		0.70		Loss of MoRF binding (P = 0.2);Loss of MoRF binding (P = 0.2);Loss of MoRF binding (P = 0.2);.;
MVP		0.57
MPC		0.068
ClinPred		0.99	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.61
Mutation Taster		=36/64	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: rs143067822; hg19: chr2-48681838;