18-45992150-A-G

Variant names:

• chr18-45992150-A-G
• NM_024430.4:c.794T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024430.4(PSTPIP2):​c.794T>C​(p.Ile265Thr) 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: 32)
• Consequence: PSTPIP2 NM_024430.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP2	NM_024430.4	c.794T>C	p.Ile265Thr	missense_variant	Exon 11 of 15	ENST00000409746.5	NP_077748.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP2	ENST00000409746.5	c.794T>C	p.Ile265Thr	missense_variant	Exon 11 of 15	1	NM_024430.4	ENSP00000387261.4
PSTPIP2	ENST00000589328.5	c.742-167T>C		intron_variant	Intron 10 of 13	1		ENSP00000468622.1
PSTPIP2	ENST00000593086.1	n.423T>C		non_coding_transcript_exon_variant	Exon 2 of 3	3
PSTPIP2	ENST00000588801.5	n.657+6644T>C		intron_variant	Intron 8 of 8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.794T>C (p.I265T) alteration is located in exon 11 (coding exon 11) of the PSTPIP2 gene. This alteration results from a T to C substitution at nucleotide position 794, causing the isoleucine (I) at amino acid position 265 to be replaced by a threonine (T). 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	Benign	0.13
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.95	P
Vest4		0.91
MutPred		0.70		Gain of disorder (P = 0.0687);
MVP		0.67
MPC		0.76
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.17
gMVP		0.88
Mutation Taster		=53/47	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: chr18-43572116;