2-48441006-C-G

Variant names:

• chr2-48441006-C-G
• rs759379106
• NM_001135629.3:c.53C>G

Variant summary

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

The NM_001135629.3(PPP1R21):​c.53C>G​(p.Ser18Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP1R21 NM_001135629.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92
• 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, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R21	NM_001135629.3	c.53C>G	p.Ser18Trp	missense_variant	Exon 1 of 22	ENST00000294952.13	NP_001129101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R21	ENST00000294952.13	c.53C>G	p.Ser18Trp	missense_variant	Exon 1 of 22	1	NM_001135629.3	ENSP00000294952.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.53C>G (p.S18W) alteration is located in exon 1 (coding exon 1) of the PPP1R21 gene. This alteration results from a C to G substitution at nucleotide position 53, causing the serine (S) at amino acid position 18 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	.;.;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Benign	0.44	N
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.5	M;M;M
PhyloP100		3.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.76
MutPred		0.60		Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);
MVP		0.31
MPC		0.061
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		-0.00080	Neutral
Varity_R		0.86
gMVP		0.26
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs759379106; hg19: chr2-48668145;