Genetic Variant PBX2:p.Glu131Lys (chr6-32188409-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002586.5(PBX2):c.391G>A(p.Glu131Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PBX2
NM_002586.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

Variant links:

Genes affected

PBX2 (HGNC:8633): (PBX homeobox 2) This gene encodes a ubiquitously expressed member of the TALE/PBX homeobox family. It was identified by its similarity to a homeobox gene which is involved in t(1;19) translocation in acute pre-B-cell leukemias. This protein is a transcriptional activator which binds to the TLX1 promoter. The gene is located within the major histocompatibility complex (MHC) on chromosome 6. [provided by RefSeq, Jul 2008]

PBX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX2	NM_002586.5 link	c.391G>A	p.Glu131Lys	missense_variant	Exon 3 of 9	ENST00000375050.6	NP_002577.2	P40425A0A024RCR3
PBX2	XM_047418839.1 link	c.46G>A	p.Glu16Lys	missense_variant	Exon 2 of 8		XP_047274795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PBX2	ENST00000375050.6 link	c.391G>A	p.Glu131Lys	missense_variant	Exon 3 of 9	1	NM_002586.5	ENSP00000364190.3	P40425
PBX2	ENST00000478678.5 link	n.418G>A		non_coding_transcript_exon_variant	Exon 3 of 6	1
PBX2	ENST00000480254.1 link	n.451G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
PBX2	ENST00000496171.1 link	n.408G>A		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248406

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.391G>A (p.E131K) alteration is located in exon 3 (coding exon 3) of the PBX2 gene. This alteration results from a G to A substitution at nucleotide position 391, causing the glutamic acid (E) at amino acid position 131 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

Pathogenic

0.98

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.13

Sift

Uncertain

0.027

Sift4G

Uncertain

0.038

Polyphen

0.86

Vest4

0.55

MutPred

0.51

Gain of ubiquitination at E131 (P = 0.006);

MVP

0.56

MPC

1.6

ClinPred

0.97

GERP RS

5.0

Varity_R

0.31

gMVP

0.76

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