2-48454692-T-G

Variant names:

• chr2-48454692-T-G
• NM_001135629.3:c.224T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001135629.3(PPP1R21):​c.224T>G​(p.Leu75Arg) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L75I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP1R21 NM_001135629.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.72
• 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
• PP5: Variant 2-48454692-T-G is Pathogenic according to our data. Variant chr2-48454692-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 3393503.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R21	NM_001135629.3	c.224T>G	p.Leu75Arg	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.224T>G	p.Leu75Arg	missense_variant	Exon 3 of 22	1	NM_001135629.3	ENSP00000294952.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities Pathogenic:1

Dec 16, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	.;.;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.8	L;L;L;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.056	T;T;T;D
Polyphen		1.0	D;.;D;.
Vest4		0.93
MutPred		0.58		Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);.;
MVP		0.46
MPC		0.066
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.40
Mutation Taster		=52/48	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

hg19: chr2-48681831;