6-32189876-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002586.5(PBX2):c.40G>T(p.Gly14Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000227 in 1,322,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: PBX2 NM_002586.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25342843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PBX2	NM_002586.5	c.40G>T	p.Gly14Cys	missense_variant	1/9	ENST00000375050.6
PBX2	XM_047418839.1	c.-232G>T		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PBX2	ENST00000375050.6	c.40G>T	p.Gly14Cys	missense_variant	1/9	1	NM_002586.5	P1
PBX2	ENST00000478678.5	n.67G>T		non_coding_transcript_exon_variant	1/6	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000227 AC: 3 AN: 1322960 Hom.: 0 Cov.: 29 AF XY: 0.00000307 AC XY: 2 AN XY: 650878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000288

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.40G>T (p.G14C) alteration is located in exon 1 (coding exon 1) of the PBX2 gene. This alteration results from a G to T substitution at nucleotide position 40, causing the glycine (G) at amino acid position 14 to be replaced by a cysteine (C). 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	0.16
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.45	N
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.51	N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.27
Sift	Benign	0.094	T
Sift4G	Uncertain	0.012	D
Polyphen		0.0	B
Vest4		0.27
MutPred		0.25		Loss of sheet (P = 0.0817);
MVP		0.71
MPC		0.75
ClinPred		0.56	D
GERP RS		3.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.4
Varity_R		0.29
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-32157653;