Variant chr12-120215568-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001385981.1(PXN):c.2395G>A(p.Glu799Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000858 in 1,594,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 0 hom. )

Consequence

PXN
NM_001385981.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0160

Variant links:

Genes affected

PXN (HGNC:9718): (paxillin) This gene encodes a cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix (focal adhesion). Alternatively spliced transcript variants encoding different isoforms have been described for this gene. These isoforms exhibit different expression pattern, and have different biochemical, as well as physiological properties (PMID:9054445). [provided by RefSeq, Aug 2011]

PXN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02441281).

BS2

High AC in GnomAd4 at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PXN	NM_001385981.1 linkuse as main transcript	c.2395G>A	p.Glu799Lys	missense_variant	10/15	ENST00000637617.2	NP_001372910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PXN	ENST00000637617.2 linkuse as main transcript	c.2395G>A	p.Glu799Lys	missense_variant	10/15	5	NM_001385981.1	ENSP00000489840	A2

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000380

AC:

AN:

229214

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

125870

show subpopulations

Gnomad AFR exome

AF:

0.0000679

Gnomad AMR exome

AF:

0.0000940

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000793

Gnomad OTH exome

AF:

0.000178

GnomAD4 exome

AF:

0.000893

AC:

1288

AN:

1442384

Hom.:

Cov.:

AF XY:

0.000851

AC XY:

610

AN XY:

716658

show subpopulations

Gnomad4 AFR exome

AF:

0.0000916

Gnomad4 AMR exome

AF:

0.000120

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000202

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.000537

GnomAD4 genome

AF:

0.000532

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000686

Hom.:

Bravo

AF:

0.000499

ExAC

AF:

0.000434

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.925G>A (p.E309K) alteration is located in exon 7 (coding exon 7) of the PXN gene. This alteration results from a G to A substitution at nucleotide position 925, causing the glutamic acid (E) at amino acid position 309 to be replaced by a lysine (K). 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

0.080

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T;T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.70

T;T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.024

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D;D;N;N;N

PROVEAN

Benign

-0.47

N;N;.;.

REVEL

Benign

0.070

Sift

Benign

0.78

T;T;.;.

Sift4G

Benign

0.84

T;T;.;.

Polyphen

0.012

B;.;.;.

Vest4

0.38

MVP

0.57

ClinPred

0.026

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over