18-45990755-T-C

Variant names:

• chr18-45990755-T-C
• rs2051520804
• NM_024430.4:c.922A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024430.4(PSTPIP2):​c.922A>G​(p.Arg308Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSTPIP2 NM_024430.4 missense, splice_region
• Scores: Splicing: ADA: 0.7897
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80
• Publications: 0 publications found

Genes affected

PSTPIP2 (HGNC:9581): (proline-serine-threonine phosphatase interacting protein 2) Predicted to enable actin filament binding activity. Predicted to be involved in actin filament polymerization. Predicted to be located in cytoskeleton and membrane. Predicted to be active in actin filament; cytoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP2	NM_024430.4	c.922A>G	p.Arg308Gly	missense_variant, splice_region_variant	Exon 13 of 15	ENST00000409746.5	NP_077748.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP2	ENST00000409746.5	c.922A>G	p.Arg308Gly	missense_variant, splice_region_variant	Exon 13 of 15	1	NM_024430.4	ENSP00000387261.4
PSTPIP2	ENST00000589328.5	c.825A>G	p.Gly275Gly	splice_region_variant, synonymous_variant	Exon 12 of 14	1		ENSP00000468622.1
PSTPIP2	ENST00000588801.5	n.658-6157A>G		intron_variant	Intron 8 of 8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.922A>G (p.R308G) alteration is located in exon 13 (coding exon 13) of the PSTPIP2 gene. This alteration results from a A to G substitution at nucleotide position 922, causing the arginine (R) at amino acid position 308 to be replaced by a glycine (G). 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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.77	T
PhyloP100		1.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.18
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.29		Loss of methylation at R308 (P = 0.0258);
MVP		0.63
MPC		1.2
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.75
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.79
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.070		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: rs2051520804; hg19: chr18-43570721;