Genetic Variant PSTPIP2:p.Gly8Glu (chr18-46072166-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024430.4(PSTPIP2):c.23G>A(p.Gly8Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000977 in 1,536,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

PSTPIP2
NM_024430.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.49

Publications

0 publications found

Variant links:

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]

PSTPIP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016234696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP2	NM_024430.4 link	c.23G>A	p.Gly8Glu	missense_variant	Exon 1 of 15	ENST00000409746.5	NP_077748.3	Q9H939-1A0A0S2Z4R2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PSTPIP2	ENST00000409746.5 link	c.23G>A	p.Gly8Glu	missense_variant	Exon 1 of 15	1	NM_024430.4	ENSP00000387261.4	Q9H939-1
PSTPIP2	ENST00000589328.5 link	c.23G>A	p.Gly8Glu	missense_variant	Exon 1 of 14	1		ENSP00000468622.1	Q9H939-2
PSTPIP2	ENST00000587042.1 link	n.107G>A		non_coding_transcript_exon_variant	Exon 1 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000727

AC:

AN:

137582

AF XY:

0.0000814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000383

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000939

AC:

AN:

1383756

Hom.:

Cov.:

AF XY:

0.0000117

AC XY:

AN XY:

682386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29486

American (AMR)

AF:

0.00

AC:

AN:

34330

Ashkenazi Jewish (ASJ)

AF:

0.000364

AC:

AN:

24720

East Asian (EAS)

AF:

0.00

AC:

AN:

34276

South Asian (SAS)

AF:

0.00

AC:

AN:

77068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4906

European-Non Finnish (NFE)

AF:

0.00000279

AC:

AN:

1073440

Other (OTH)

AF:

0.0000174

AC:

AN:

57386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000959

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.23G>A (p.G8E) alteration is located in exon 1 (coding exon 1) of the PSTPIP2 gene. This alteration results from a G to A substitution at nucleotide position 23, causing the glycine (G) at amino acid position 8 to be replaced by a glutamic acid (E). 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

Benign

-0.31

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.030

.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.64

N;N

PhyloP100

-1.5

PrimateAI

Uncertain

0.53

PROVEAN

Benign

1.3

.;N

REVEL

Benign

0.059

Sift

Benign

0.14

.;T

Sift4G

Benign

0.93

T;T

Polyphen

0.0020

B;B

Vest4

0.18

MVP

0.21

MPC

0.44

ClinPred

0.075

GERP RS

-1.9

PromoterAI

0.030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.10

gMVP

0.40

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

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chr18-46072166-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over